Receptors, Cannabinoid: A class of G-protein-coupled receptors that are specific for CANNABINOIDS such as those derived from CANNABIS. They also bind a structurally distinct class of endogenous factors referred to as ENDOCANNABINOIDS. The receptor class may play a role in modulating the release of signaling molecules such as NEUROTRANSMITTERS and CYTOKINES.Cannabinoid Receptor Modulators: Compounds that interact with and modulate the activity of CANNABINOID RECEPTORS.Receptor, Cannabinoid, CB1: A subclass of cannabinoid receptor found primarily on central and peripheral NEURONS where it may play a role modulating NEUROTRANSMITTER release.Receptor, Cannabinoid, CB2: A subclass of cannabinoid receptor found primarily on immune cells where it may play a role modulating release of CYTOKINES.Cannabinoid Receptor Agonists: Compounds that interact with and stimulate the activity of CANNABINOID RECEPTORS.Selective Estrogen Receptor Modulators: A structurally diverse group of compounds distinguished from ESTROGENS by their ability to bind and activate ESTROGEN RECEPTORS but act as either an agonist or antagonist depending on the tissue type and hormonal milieu. They are classified as either first generation because they demonstrate estrogen agonist properties in the ENDOMETRIUM or second generation based on their patterns of tissue specificity. (Horm Res 1997;48:155-63)Cannabinoids: Compounds having the cannabinoid structure. They were originally extracted from Cannabis sativa L. The most pharmacologically active constituents are TETRAHYDROCANNABINOL; CANNABINOL; and CANNABIDIOL.Cannabinoid Receptor Antagonists: Compounds that inhibit or block the activity of CANNABINOID RECEPTORS.Endocannabinoids: Fatty acid derivatives that have specificity for CANNABINOID RECEPTORS. They are structurally distinct from CANNABINOIDS and were originally discovered as a group of endogenous CANNABINOID RECEPTOR AGONISTS.Cyclohexanols: Monohydroxy derivatives of cyclohexanes that contain the general formula R-C6H11O. They have a camphorlike odor and are used in making soaps, insecticides, germicides, dry cleaning, and plasticizers.Benzoxazines: OXAZINES with a fused BENZENE ring.Dronabinol: A psychoactive compound extracted from the resin of Cannabis sativa (marihuana, hashish). The isomer delta-9-tetrahydrocannabinol (THC) is considered the most active form, producing characteristic mood and perceptual changes associated with this compound.Pyrazoles: Azoles of two nitrogens at the 1,2 positions, next to each other, in contrast with IMIDAZOLES in which they are at the 1,3 positions.Polyunsaturated Alkamides: Amides composed of unsaturated aliphatic FATTY ACIDS linked with AMINES by an amide bond. They are most prominent in ASTERACEAE; PIPERACEAE; and RUTACEAE; and also found in ARISTOLOCHIACEAE; BRASSICACEAE; CONVOLVULACEAE; EUPHORBIACEAE; MENISPERMACEAE; POACEAE; and SOLANACEAE. They are recognized by their pungent taste and for causing numbing and salivation.Raloxifene: A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue.Piperidines: A family of hexahydropyridines.Receptors, Drug: Proteins that bind specific drugs with high affinity and trigger intracellular changes influencing the behavior of cells. Drug receptors are generally thought to be receptors for some endogenous substance not otherwise specified.Naphthalenes: Two-ring crystalline hydrocarbons isolated from coal tar. They are used as intermediates in chemical synthesis, as insect repellents, fungicides, lubricants, preservatives, and, formerly, as topical antiseptics.Arachidonic AcidsMorpholinesBornanesGlycerides: GLYCEROL esterified with FATTY ACIDS.Norpregnadienes: Pregnadienes which have undergone ring contractions or are lacking carbon-18 or carbon-19.Estrogen Receptor Modulators: Substances that possess antiestrogenic actions but can also produce estrogenic effects as well. They act as complete or partial agonist or as antagonist. They can be either steroidal or nonsteroidal in structure.Cannabidiol: Compound isolated from Cannabis sativa extract.AmidohydrolasesMonoacylglycerol Lipases: An enzyme that catalyzes the hydrolysis of glycerol monoesters of long-chain fatty acids EC 3.1.1.23.Tamoxifen: One of the SELECTIVE ESTROGEN RECEPTOR MODULATORS with tissue-specific activities. Tamoxifen acts as an anti-estrogen (inhibiting agent) in the mammary tissue, but as an estrogen (stimulating agent) in cholesterol metabolism, bone density, and cell proliferation in the ENDOMETRIUM.Estrogen Antagonists: Compounds which inhibit or antagonize the action or biosynthesis of estrogenic compounds.Analgesics: Compounds capable of relieving pain without the loss of CONSCIOUSNESS.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Rats, Sprague-Dawley: A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.Cannabinol: A physiologically inactive constituent of Cannabis sativa L.GABA Modulators: Substances that do not act as agonists or antagonists but do affect the GAMMA-AMINOBUTYRIC ACID receptor-ionophore complex. GABA-A receptors (RECEPTORS, GABA-A) appear to have at least three allosteric sites at which modulators act: a site at which BENZODIAZEPINES act by increasing the opening frequency of GAMMA-AMINOBUTYRIC ACID-activated chloride channels; a site at which BARBITURATES act to prolong the duration of channel opening; and a site at which some steroids may act. GENERAL ANESTHETICS probably act at least partly by potentiating GABAergic responses, but they are not included here.ThiophenesLigands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)Cannabis: The plant genus in the Cannabaceae plant family, Urticales order, Hamamelidae subclass. The flowering tops are called many slang terms including pot, marijuana, hashish, bhang, and ganja. The stem is an important source of hemp fiber.Propylene Glycols: Derivatives of propylene glycol (1,2-propanediol). They are used as humectants and solvents in pharmaceutical preparations.Indoles: Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.Estrogen Receptor alpha: One of the ESTROGEN RECEPTORS that has marked affinity for ESTRADIOL. Its expression and function differs from, and in some ways opposes, ESTROGEN RECEPTOR BETA.Estradiol: The 17-beta-isomer of estradiol, an aromatized C18 steroid with hydroxyl group at 3-beta- and 17-beta-position. Estradiol-17-beta is the most potent form of mammalian estrogenic steroids.Receptors, Estrogen: Cytoplasmic proteins that bind estrogens and migrate to the nucleus where they regulate DNA transcription. Evaluation of the state of estrogen receptors in breast cancer patients has become clinically important.Ovariectomy: The surgical removal of one or both ovaries.Receptors, Lysosphingolipid: A subfamily of lysophospholipid receptors with specificity for LYSOSPHINGOLIPIDS such as sphingosine-1-phosphate and sphingosine phosphorylcholine.Signal Transduction: The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.Leiomyoma: A benign tumor derived from smooth muscle tissue, also known as a fibroid tumor. They rarely occur outside of the UTERUS and the GASTROINTESTINAL TRACT but can occur in the SKIN and SUBCUTANEOUS TISSUE, probably arising from the smooth muscle of small blood vessels in these tissues.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Toremifene: A first generation selective estrogen receptor modulator (SERM). Like TAMOXIFEN, it is an estrogen agonist for bone tissue and cholesterol metabolism but is antagonistic on mammary and uterine tissue.Mice, Inbred C57BLPyrrolidinesTetrahydronaphthalenes: Partially saturated 1,2,3,4-tetrahydronaphthalene compounds.Receptors, Androgen: Proteins, generally found in the CYTOPLASM, that specifically bind ANDROGENS and mediate their cellular actions. The complex of the androgen and receptor migrates to the CELL NUCLEUS where it induces transcription of specific segments of DNA.Estrogens: Compounds that interact with ESTROGEN RECEPTORS in target tissues to bring about the effects similar to those of ESTRADIOL. Estrogens stimulate the female reproductive organs, and the development of secondary female SEX CHARACTERISTICS. Estrogenic chemicals include natural, synthetic, steroidal, or non-steroidal compounds.Oximes: Compounds that contain the radical R2C=N.OH derived from condensation of ALDEHYDES or KETONES with HYDROXYLAMINE. Members of this group are CHOLINESTERASE REACTIVATORS.Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.Mice, Knockout: Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.Carbamates: Derivatives of carbamic acid, H2NC(=O)OH. Included under this heading are N-substituted and O-substituted carbamic acids. In general carbamate esters are referred to as urethanes, and polymers that include repeating units of carbamate are referred to as POLYURETHANES. Note however that polyurethanes are derived from the polymerization of ISOCYANATES and the singular term URETHANE refers to the ethyl ester of carbamic acid.Calcium Channel Blockers: A class of drugs that act by selective inhibition of calcium influx through cellular membranes.Benzofurans: Compounds that contain a BENZENE ring fused to a furan ring.Brain: The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.Androgens: Compounds that interact with ANDROGEN RECEPTORS in target tissues to bring about the effects similar to those of TESTOSTERONE. Depending on the target tissues, androgenic effects can be on SEX DIFFERENTIATION; male reproductive organs, SPERMATOGENESIS; secondary male SEX CHARACTERISTICS; LIBIDO; development of muscle mass, strength, and power.Guanosine 5'-O-(3-Thiotriphosphate): Guanosine 5'-(trihydrogen diphosphate), monoanhydride with phosphorothioic acid. A stable GTP analog which enjoys a variety of physiological actions such as stimulation of guanine nucleotide-binding proteins, phosphoinositide hydrolysis, cyclic AMP accumulation, and activation of specific proto-oncogenes.Drug Interactions: The action of a drug that may affect the activity, metabolism, or toxicity of another drug.Hippocampus: A curved elevation of GRAY MATTER extending the entire length of the floor of the TEMPORAL HORN of the LATERAL VENTRICLE (see also TEMPORAL LOBE). The hippocampus proper, subiculum, and DENTATE GYRUS constitute the hippocampal formation. Sometimes authors include the ENTORHINAL CORTEX in the hippocampal formation.Receptors, GABA-A: Cell surface proteins which bind GAMMA-AMINOBUTYRIC ACID and contain an integral membrane chloride channel. Each receptor is assembled as a pentamer from a pool of at least 19 different possible subunits. The receptors belong to a superfamily that share a common CYSTEINE loop.Benzodioxoles: Compounds based on benzene fused to oxole. They can be formed from methylated CATECHOLS such as EUGENOL.Estrogen Receptor beta: One of the ESTROGEN RECEPTORS that has greater affinity for ISOFLAVONES than ESTROGEN RECEPTOR ALPHA does. There is great sequence homology with ER alpha in the DNA-binding domain but not in the ligand binding and hinge domains.Cells, Cultured: Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.Drug Evaluation, Preclinical: Preclinical testing of drugs in experimental animals or in vitro for their biological and toxic effects and potential clinical applications.Drug Inverse Agonism: Phenomena and pharmaceutics of compounds that bind to the same receptor binding-site as an agonist (DRUG AGONISM) for that receptor but exerts the opposite pharmacological effect.Drug Design: The molecular designing of drugs for specific purposes (such as DNA-binding, enzyme inhibition, anti-cancer efficacy, etc.) based on knowledge of molecular properties such as activity of functional groups, molecular geometry, and electronic structure, and also on information cataloged on analogous molecules. Drug design is generally computer-assisted molecular modeling and does not include pharmacokinetics, dosage analysis, or drug administration analysis.Estrenes: Unsaturated derivatives of the ESTRANES with methyl groups at carbon-13, with no carbon at carbon-10, and with no more than one carbon at carbon-17. They must contain one or more double bonds.Uterine Neoplasms: Tumors or cancer of the UTERUS.CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Osteoporosis, Postmenopausal: Metabolic disorder associated with fractures of the femoral neck, vertebrae, and distal forearm. It occurs commonly in women within 15-20 years after menopause, and is caused by factors associated with menopause including estrogen deficiency.Anabolic Agents: These compounds stimulate anabolism and inhibit catabolism. They stimulate the development of muscle mass, strength, and power.Aminophenols: Phenols substituted in any position by an amino group.Binding, Competitive: The interaction of two or more substrates or ligands with the same binding site. The displacement of one by the other is used in quantitative and selective affinity measurements.TRPV Cation Channels: A subgroup of TRP cation channels named after vanilloid receptor. They are very sensitive to TEMPERATURE and hot spicy food and CAPSAICIN. They have the TRP domain and ANKYRIN repeats. Selectivity for CALCIUM over SODIUM ranges from 3 to 100 fold.Disease Models, Animal: Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.Uterus: The hollow thick-walled muscular organ in the female PELVIS. It consists of the fundus (the body) which is the site of EMBRYO IMPLANTATION and FETAL DEVELOPMENT. Beyond the isthmus at the perineal end of fundus, is CERVIX UTERI (the neck) opening into VAGINA. Beyond the isthmi at the upper abdominal end of fundus, are the FALLOPIAN TUBES.Structure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Androgen Receptor Antagonists: Compounds that bind to and inhibit the activation of ANDROGEN RECEPTORS.Ethanolamines: AMINO ALCOHOLS containing the ETHANOLAMINE; (-NH2CH2CHOH) group and its derivatives.Radioligand Assay: Quantitative determination of receptor (binding) proteins in body fluids or tissue using radioactively labeled binding reagents (e.g., antibodies, intracellular receptors, plasma binders).Receptors, Progesterone: Specific proteins found in or on cells of progesterone target tissues that specifically combine with progesterone. The cytosol progesterone-receptor complex then associates with the nucleic acids to initiate protein synthesis. There are two kinds of progesterone receptors, A and B. Both are induced by estrogen and have short half-lives.Marijuana Abuse: The excessive use of marijuana with associated psychological symptoms and impairment in social or occupational functioning.Ovulation Inhibition: Blocking the process leading to OVULATION. Various factors are known to inhibit ovulation, such as neuroendocrine, psychological, and pharmacological agents.Synaptic Transmission: The communication from a NEURON to a target (neuron, muscle, or secretory cell) across a SYNAPSE. In chemical synaptic transmission, the presynaptic neuron releases a NEUROTRANSMITTER that diffuses across the synaptic cleft and binds to specific synaptic receptors, activating them. The activated receptors modulate specific ion channels and/or second-messenger systems in the postsynaptic cell. In electrical synaptic transmission, electrical signals are communicated as an ionic current flow across ELECTRICAL SYNAPSES.Piper nigrum: A plant species in the PIPERACEAE plant family. It is a common spice on foods and is used medicinally to increase gastrointestinal assimilation of other supplements and drugs. Piperine is a key component. Black pepper is picked unripe and heaped for a few days to ferment. White Pepper is the ripe fruit dehulled by maceration in water.Cyclohexanes: Six-carbon alicyclic hydrocarbons.ResorcinolsBehavior, Animal: The observable response an animal makes to any situation.gamma-Aminobutyric Acid: The most common inhibitory neurotransmitter in the central nervous system.RNA, Messenger: RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.Hormone Antagonists: Chemical substances which inhibit the function of the endocrine glands, the biosynthesis of their secreted hormones, or the action of hormones upon their specific sites.Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds.Endometrium: The mucous membrane lining of the uterine cavity that is hormonally responsive during the MENSTRUAL CYCLE and PREGNANCY. The endometrium undergoes cyclic changes that characterize MENSTRUATION. After successful FERTILIZATION, it serves to sustain the developing embryo.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Patch-Clamp Techniques: An electrophysiologic technique for studying cells, cell membranes, and occasionally isolated organelles. All patch-clamp methods rely on a very high-resistance seal between a micropipette and a membrane; the seal is usually attained by gentle suction. The four most common variants include on-cell patch, inside-out patch, outside-out patch, and whole-cell clamp. Patch-clamp methods are commonly used to voltage clamp, that is control the voltage across the membrane and measure current flow, but current-clamp methods, in which the current is controlled and the voltage is measured, are also used.Protein Binding: The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.Breast Neoplasms: Tumors or cancer of the human BREAST.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Gene Expression Regulation: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from DRUG RESISTANCE wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from MAXIMUM TOLERATED DOSE and NO-OBSERVED-ADVERSE-EFFECT LEVEL.Hallucinogens: Drugs capable of inducing illusions, hallucinations, delusions, paranoid ideations, and other alterations of mood and thinking. Despite the name, the feature that distinguishes these agents from other classes of drugs is their capacity to induce states of altered perception, thought, and feeling that are not experienced otherwise.Mice, Inbred ICRCapsaicin: An alkylamide found in CAPSICUM that acts at TRPV CATION CHANNELS.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Cell Line, Tumor: A cell line derived from cultured tumor cells.Cerebellum: The part of brain that lies behind the BRAIN STEM in the posterior base of skull (CRANIAL FOSSA, POSTERIOR). It is also known as the "little brain" with convolutions similar to those of CEREBRAL CORTEX, inner white matter, and deep cerebellar nuclei. Its function is to coordinate voluntary movements, maintain balance, and learn motor skills.Allosteric Regulation: The modification of the reactivity of ENZYMES by the binding of effectors to sites (ALLOSTERIC SITES) on the enzymes other than the substrate BINDING SITES.Bone Density Conservation Agents: Agents that inhibit BONE RESORPTION and/or favor BONE MINERALIZATION and BONE REGENERATION. They are used to heal BONE FRACTURES and to treat METABOLIC BONE DISEASES such as OSTEOPOROSIS.Presynaptic Terminals: The distal terminations of axons which are specialized for the release of neurotransmitters. Also included are varicosities along the course of axons which have similar specializations and also release transmitters. Presynaptic terminals in both the central and peripheral nervous systems are included.Amides: Organic compounds containing the -CO-NH2 radical. Amides are derived from acids by replacement of -OH by -NH2 or from ammonia by the replacement of H by an acyl group. (From Grant & Hackh's Chemical Dictionary, 5th ed)Pertussis Toxin: One of the virulence factors produced by BORDETELLA PERTUSSIS. It is a multimeric protein composed of five subunits S1 - S5. S1 contains mono ADPribose transferase activity.Pain: An unpleasant sensation induced by noxious stimuli which are detected by NERVE ENDINGS of NOCICEPTIVE NEURONS.Hyperalgesia: An increased sensation of pain or discomfort produced by mimimally noxious stimuli due to damage to soft tissue containing NOCICEPTORS or injury to a peripheral nerve.Antineoplastic Agents, Hormonal: Antineoplastic agents that are used to treat hormone-sensitive tumors. Hormone-sensitive tumors may be hormone-dependent, hormone-responsive, or both. A hormone-dependent tumor regresses on removal of the hormonal stimulus, by surgery or pharmacological block. Hormone-responsive tumors may regress when pharmacologic amounts of hormones are administered regardless of whether previous signs of hormone sensitivity were observed. The major hormone-responsive cancers include carcinomas of the breast, prostate, and endometrium; lymphomas; and certain leukemias. (From AMA Drug Evaluations Annual 1994, p2079)Gonanes: Steroids containing the fundamental tetracyclic unit with no methyl groups at C-10 and C-13 and with no side chain at C-17. The concept includes both saturated and unsaturated derivatives.AnilidesNeuroprotective Agents: Drugs intended to prevent damage to the brain or spinal cord from ischemia, stroke, convulsions, or trauma. Some must be administered before the event, but others may be effective for some time after. They act by a variety of mechanisms, but often directly or indirectly minimize the damage produced by endogenous excitatory amino acids.Palmitic Acids: A group of 16-carbon fatty acids that contain no double bonds.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Stereoisomerism: The phenomenon whereby compounds whose molecules have the same number and kind of atoms and the same atomic arrangement, but differ in their spatial relationships. (From McGraw-Hill Dictionary of Scientific and Technical Terms, 5th ed)Androgen Antagonists: Compounds which inhibit or antagonize the biosynthesis or actions of androgens.Blotting, Western: Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.Receptors, G-Protein-Coupled: The largest family of cell surface receptors involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC G-PROTEINS.Orchiectomy: The surgical removal of one or both testicles.Keratin-13: A type I keratin that is found associated with the KERATIN-4 in the internal stratified EPITHELIUM. Defects in gene for keratin 13 cause HEREDITARY MUCOSAL LEUKOKERATOSIS.Immunohistochemistry: Histochemical localization of immunoreactive substances using labeled antibodies as reagents.Contraceptive Agents, Male: Chemical substances or agents with contraceptive activity in males. Use for male contraceptive agents in general or for which there is no specific heading.Medical Marijuana: Product of the CANNABIS plant, CANNABINOIDS, or synthetic derivatives thereof, used in the treatment of a wide range of clinical symptoms.Phenylmethylsulfonyl Fluoride: An enzyme inhibitor that inactivates IRC-50 arvin, subtilisin, and the fatty acid synthetase complex.Sphingosine: An amino alcohol with a long unsaturated hydrocarbon chain. Sphingosine and its derivative sphinganine are the major bases of the sphingolipids in mammals. (Dorland, 28th ed)Excitatory Postsynaptic Potentials: Depolarization of membrane potentials at the SYNAPTIC MEMBRANES of target neurons during neurotransmission. Excitatory postsynaptic potentials can singly or in summation reach the trigger threshold for ACTION POTENTIALS.GTP-Binding Protein alpha Subunits, Gi-Go: A family of heterotrimeric GTP-binding protein alpha subunits that were originally identified by their ability to inhibit ADENYLYL CYCLASES. Members of this family can couple to beta and gamma G-protein subunits that activate POTASSIUM CHANNELS. The Gi-Go part of the name is also spelled Gi/Go.Neural Inhibition: The function of opposing or restraining the excitation of neurons or their target excitable cells.Cyclic AMP: An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.Cricetulus: A genus of the family Muridae consisting of eleven species. C. migratorius, the grey or Armenian hamster, and C. griseus, the Chinese hamster, are the two species used in biomedical research.Analgesics, Non-Narcotic: A subclass of analgesic agents that typically do not bind to OPIOID RECEPTORS and are not addictive. Many non-narcotic analgesics are offered as NONPRESCRIPTION DRUGS.Receptors, Opioid, mu: A class of opioid receptors recognized by its pharmacological profile. Mu opioid receptors bind, in decreasing order of affinity, endorphins, dynorphins, met-enkephalin, and leu-enkephalin. They have also been shown to be molecular receptors for morphine.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Estradiol Congeners: Steroidal compounds related to ESTRADIOL, the major mammalian female sex hormone. Estradiol congeners include important estradiol precursors in the biosynthetic pathways, metabolites, derivatives, and synthetic steroids with estrogenic activities.Benzothiadiazines: Heterocyclic compounds of a ring with SULFUR and two NITROGEN atoms fused to a BENZENE ring. Members inhibit SODIUM-POTASSIUM-CHLORIDE SYMPORTERS and are used as DIURETICS.Marijuana Smoking: Inhaling and exhaling the smoke from CANNABIS.Psychotropic Drugs: A loosely defined grouping of drugs that have effects on psychological function. Here the psychotropic agents include the antidepressive agents, hallucinogens, and tranquilizing agents (including the antipsychotics and anti-anxiety agents).Benzodiazepines: A group of two-ring heterocyclic compounds consisting of a benzene ring fused to a diazepine ring.Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis (OSTEOPOROSIS, POSTMENOPAUSAL) and age-related or senile osteoporosis.Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid is the most common excitatory neurotransmitter in the CENTRAL NERVOUS SYSTEM.Postmenopause: The physiological period following the MENOPAUSE, the permanent cessation of the menstrual life.Colforsin: Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland.Designer Drugs: Drugs designed and synthesized, often for illegal street use, by modification of existing drug structures (e.g., amphetamines). Of special interest are MPTP (a reverse ester of meperidine), MDA (3,4-methylenedioxyamphetamine), and MDMA (3,4-methylenedioxymethamphetamine). Many drugs act on the aminergic system, the physiologically active biogenic amines.Motor Activity: The physical activity of a human or an animal as a behavioral phenomenon.Anisoles: A group of compounds that are derivatives of methoxybenzene and contain the general formula R-C7H7O.Tumor Cells, Cultured: Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.Periaqueductal Gray: Central gray matter surrounding the CEREBRAL AQUEDUCT in the MESENCEPHALON. Physiologically it is probably involved in RAGE reactions, the LORDOSIS REFLEX; FEEDING responses, bladder tonus, and pain.Nicotinic Acids: 2-, 3-, or 4-Pyridinecarboxylic acids. Pyridine derivatives substituted with a carboxy group at the 2-, 3-, or 4-position. The 3-carboxy derivative (NIACIN) is active as a vitamin.Self Administration: Administration of a drug or chemical by the individual under the direction of a physician. It includes administration clinically or experimentally, by human or animal.Neuralgia: Intense or aching pain that occurs along the course or distribution of a peripheral or cranial nerve.Cinchona Alkaloids: Alkaloids extracted from various species of Cinchona.Apoptosis: One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.Substance Withdrawal Syndrome: Physiological and psychological symptoms associated with withdrawal from the use of a drug after prolonged administration or habituation. The concept includes withdrawal from smoking or drinking, as well as withdrawal from an administered drug.Chromatography, High Pressure Liquid: Liquid chromatographic techniques which feature high inlet pressures, high sensitivity, and high speed.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Organ Specificity: Characteristic restricted to a particular organ of the body, such as a cell type, metabolic response or expression of a particular protein or antigen.GABAergic Neurons: Neurons whose primary neurotransmitter is GAMMA-AMINOBUTYRIC ACID.Molecular Conformation: The characteristic three-dimensional shape of a molecule.Pain Measurement: Scales, questionnaires, tests, and other methods used to assess pain severity and duration in patients or experimental animals to aid in diagnosis, therapy, and physiological studies.Transfection: The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.TritiumArrestins: Regulatory proteins that down-regulate phosphorylated G-protein membrane receptors, including rod and cone photoreceptors and adrenergic receptors.Diazepam: A benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant, and amnesic properties and a long duration of action. Its actions are mediated by enhancement of GAMMA-AMINOBUTYRIC ACID activity.GTP-Binding Proteins: Regulatory proteins that act as molecular switches. They control a wide range of biological processes including: receptor signaling, intracellular signal transduction pathways, and protein synthesis. Their activity is regulated by factors that control their ability to bind to and hydrolyze GTP to GDP. EC 3.6.1.-.Drug Discovery: The process of finding chemicals for potential therapeutic use.Microglia: The third type of glial cell, along with astrocytes and oligodendrocytes (which together form the macroglia). Microglia vary in appearance depending on developmental stage, functional state, and anatomical location; subtype terms include ramified, perivascular, ameboid, resting, and activated. Microglia clearly are capable of phagocytosis and play an important role in a wide spectrum of neuropathologies. They have also been suggested to act in several other roles including in secretion (e.g., of cytokines and neural growth factors), in immunological processing (e.g., antigen presentation), and in central nervous system development and remodeling.Limbic System: A set of forebrain structures common to all mammals that is defined functionally and anatomically. It is implicated in the higher integration of visceral, olfactory, and somatic information as well as homeostatic responses including fundamental survival behaviors (feeding, mating, emotion). For most authors, it includes the AMYGDALA; EPITHALAMUS; GYRUS CINGULI; hippocampal formation (see HIPPOCAMPUS); HYPOTHALAMUS; PARAHIPPOCAMPAL GYRUS; SEPTAL NUCLEI; anterior nuclear group of thalamus, and portions of the basal ganglia. (Parent, Carpenter's Human Neuroanatomy, 9th ed, p744; NeuroNames, http://rprcsgi.rprc.washington.edu/neuronames/index.html (September 2, 1998)).Corpus Striatum: Striped GRAY MATTER and WHITE MATTER consisting of the NEOSTRIATUM and paleostriatum (GLOBUS PALLIDUS). It is located in front of and lateral to the THALAMUS in each cerebral hemisphere. The gray substance is made up of the CAUDATE NUCLEUS and the lentiform nucleus (the latter consisting of the GLOBUS PALLIDUS and PUTAMEN). The WHITE MATTER is the INTERNAL CAPSULE.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Myometrium: The smooth muscle coat of the uterus, which forms the main mass of the organ.Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, DYSPAREUNIA, and progressive development of OSTEOPOROSIS. This may also include the use of progestational agents in combination therapy.Phytoestrogens: PLANT EXTRACTS and compounds, primarily ISOFLAVONES, that mimic or modulate endogenous estrogens, usually by binding to ESTROGEN RECEPTORS.Inhibitory Postsynaptic Potentials: Hyperpolarization of membrane potentials at the SYNAPTIC MEMBRANES of target neurons during NEUROTRANSMISSION. They are local changes which diminish responsiveness to excitatory signals.Electric Stimulation: Use of electric potential or currents to elicit biological responses.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Bone and Bones: A specialized CONNECTIVE TISSUE that is the main constituent of the SKELETON. The principle cellular component of bone is comprised of OSTEOBLASTS; OSTEOCYTES; and OSTEOCLASTS, while FIBRILLAR COLLAGENS and hydroxyapatite crystals form the BONE MATRIX.Eurotium: A genus of ascomycetous fungi in the family Trichocomaceae, order EUROTIALES. Health effects, allergenicity, and toxicity of Eurotium are closely related to its anamorph ASPERGILLUS.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Benzamides: BENZOIC ACID amides.Interneurons: Most generally any NEURONS which are not motor or sensory. Interneurons may also refer to neurons whose AXONS remain within a particular brain region in contrast to projection neurons, which have axons projecting to other brain regions.Amygdala: Almond-shaped group of basal nuclei anterior to the INFERIOR HORN OF THE LATERAL VENTRICLE of the TEMPORAL LOBE. The amygdala is part of the limbic system.Gastrointestinal Motility: The motor activity of the GASTROINTESTINAL TRACT.Organ Size: The measurement of an organ in volume, mass, or heaviness.Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species.Anticarcinogenic Agents: Agents that reduce the frequency or rate of spontaneous or induced tumors independently of the mechanism involved.Zanthoxylum: A plant genus of the family RUTACEAE. Some members of Zanthoxylum are reclassified from ELEUTHEROCOCCUS, Melicope, and EVODIA. The twigs are used as dental brushing sticks (TOOTHBRUSHING). Most plants that are called Fagara have been reclassified as Zanthoxylum, however some Fagara were reclassified to MELICOPE (also in the Rutacea family) or to GLEDITSIA (a genus in the FABACEAE family).Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.GABA Agonists: Endogenous compounds and drugs that bind to and activate GAMMA-AMINOBUTYRIC ACID receptors (RECEPTORS, GABA).Oleic Acids: A group of fatty acids that contain 18 carbon atoms and a double bond at the omega 9 carbon.Mass Spectrometry: An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers.
Biosynthesis and inactivation of the endocannabinoid 2-arachidonoylglycerol in circulating and tumoral macrophages. (1/954)
The stimulus-induced biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG) in intact mouse J774 macrophages and the inactivation of 2-AG by the same cells or by rat circulating macrophages was studied. By using gas chromatography-mass spectrometry, we found that ionomycin (5 microM) and lipopolysaccharide (LPS, 200 microg x mL-1) cause a 24-fold and 2.5-fold stimulation of 2-AG levels in J774 cells, respectively, thus providing unprecedented evidence that this cannabimimetic metabolite can be synthesized by macrophages. In J774 cells, LPS also induced a 7.8-fold increase of the levels of the other endocannabinoid, anandamide, and, in rat circulating macrophages, an almost twofold increase of 2-AG levels. Extracellular [3H]2-AG was cleared from the medium of intact J774 macrophages (t1/2 = 19-28 min) and esterified to phospholipids, diacylglycerols and triglycerides or hydrolyzed to [3H]arachidonic acid and glycerol. These catabolic processes were attenuated differentially by various enzyme inhibitors. Rat circulating macrophages were shown to contain enzymatic activities for the hydrolysis of 2-AG, including: (a) fatty acid amide hydrolase (FAAH), the enzyme responsible for anandamide breakdown and previously shown to catalyse also 2-AG hydrolysis, and (b) a 2-AG hydrolase activity different from FAAH and down-regulated by LPS. High levels of FAAH mRNA were found in circulating macrophages but not platelets, which, however, contain a 2-AG hydrolase. Both platelets and macrophages were shown to express the mRNA for the CB1 cannabinoid receptor. A macrophage 2-AG hydrolase with apparent Km = 110 microM and Vmax = 7.9 nmol x min-1 x (mg protein)-1 was partially characterized in J774 cells and found to exhibit an optimal pH of 6-7 and little or no sensitivity to typical FAAH inhibitors. These findings demonstrate for the first time that macrophages participate in the homeostasis of the hypotensive and immunomodulatory endocannabinoid 2-AG through metabolic mechanisms that are subject to regulation. (+info)The endothelial component of cannabinoid-induced relaxation in rabbit mesenteric artery depends on gap junctional communication. (2/954)
1. We have shown that the endocannabinoid anandamide and its stable analogue methanandamide relax rings of rabbit superior mesenteric artery through endothelium-dependent and -independent mechanisms that are unaffected by blockade of NO synthase and cyclooxygenase. 2. The endothelium-dependent component of the responses was attenuated by the gap junction inhibitor 18alpha-glycyrrhetinic acid (18alpha-GA; 50 microM), and a synthetic connexin-mimetic peptide homologous to the extracellular Gap 27 sequence of connexin 43 (43Gap 27, SRPTEKTIFII; 300 microM). By contrast, the corresponding connexin 40 peptide (40Gap 27, SRPTEKNVFIV) was inactive. 3. The cannabinoid CB1 receptor antagonist SR141716A (10 microM) also attenuated endothelium-dependent relaxations but this inhibition was not observed with the CB1 receptor antagonist LY320135 (10 microM). Furthermore, SR141716A mimicked the effects of 43Gap 27 peptide in blocking Lucifer Yellow dye transfer between coupled COS-7 cells (a monkey fibroblast cell line), whereas LY320135 was without effect, thus suggesting that the action of SR141716A was directly attributable to effects on gap junctions. 4. The endothelium-dependent component of cannabinoid-induced relaxation was also attenuated by AM404 (10 microM), an inhibitor of the high-affinity anandamide transporter, which was without effect on dye transfer. 5. Taken together, the findings suggest that cannabinoids derived from arachidonic acid gain access to the endothelial cytosol via a transporter mechanism and subsequently stimulate relaxation by promoting diffusion of an to adjacent smooth muscle cells via gap junctions. 6. Relaxations of endothelium-denuded preparations to anandamide and methanandamide were unaffected by 43Gap 27 peptide, 18alpha-GA, SR141716A, AM404 and indomethacin and their genesis remains to be established. (+info)Comparison of novel cannabinoid partial agonists and SR141716A in the guinea-pig small intestine. (3/954)
The controversial nature of the CB(1) receptor antagonist, SR141716A, in the guinea-pig small intestine was investigated by comparing it with four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): O-1184, O-1238, O-584 and O-1315. These compounds (10 - 1000 nM) inhibited the electrically-evoked contractions with a rank order of potency of O-1238>O-1184>O-584>O-1315. Log concentration-response curves for O-1238, O-1184 and O-1315 were significantly shifted to the right by SR141716A and the maxima were significantly less than that of the CB(1) agonist, WIN55212-2, an indication of partial agonism. Partial saturation of the triple bond in O-1184 to a cis double bond (O-1238) increased its potency as an agonist (pEC(50) from 6.42 to 7.63) and as an antagonist of WIN55212-2, (pK(B), from 8.36 to 9.49). Substitution of the terminal azide group by an ethyl group (O-584) or removal of the phenolic hydroxyl group (O-1315) had no significant effect on the agonist or antagonist potency. None of these analogues increased the twitch response in a manner resembling that of SR141716A. O-1184 (10 and 100 nM) shifted the log concentration-response curve of WIN55212-2 for inhibition of the twitch responses to the right with pK(B) values of 8.29 and 8.38, respectively. We conclude that these Delta(8)-THC analogues behave as partial agonists rather than silent antagonists at CB(1) binding sites in this tissue. There was no evidence of antagonism of endocannabinoids thus supporting the hypothesis that, in this tissue, SR141716A is an inverse agonist of constitutively active CB(1) receptors. (+info)Reversal of dopamine D(2) receptor responses by an anandamide transport inhibitor. (4/954)
We characterized the pharmacological properties of the anandamide transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404) in rats and investigated the effects of this drug on behavioral responses associated with activation of dopamine D(2) family receptors. Rat brain slices accumulated [(3)H]anandamide via a high-affinity transport mechanism that was blocked by AM404. When administered alone in vivo, AM404 caused a mild and slow-developing hypokinesia that was significant 60 min after intracerebroventricular injection of the drug and was reversed by the CB1 cannabinoid receptor antagonist SR141716A. AM404 produced no significant catalepsy or analgesia, two typical effects of direct-acting cannabinoid agonists. However, AM404 prevented the stereotypic yawning produced by systemic administration of a low dose of apomorphine, an effect that was dose-dependent and blocked by SR141716A. Furthermore, AM404 reduced the stimulation of motor behaviors elicited by the selective D(2) family receptor agonist quinpirole. Finally, AM404 reduced hyperactivity in juvenile spontaneously hypertensive rats, a putative model of attention deficit hyperactivity disorder. The results support a primary role of the endocannabinoid system in the regulation of psychomotor activity and point to anandamide transport as a potential target for neuropsychiatric medicines. (+info)Endocannabinoid 2-arachidonyl glycerol is a full agonist through human type 2 cannabinoid receptor: antagonism by anandamide. (5/954)
The endocannabinoids anandamide and 2-arachidonyl glycerol (2-AG) bind to G protein-coupled central and peripheral cannabinoid receptors CB1 and CB2, respectively. Due to the relatively high expression of the CB2 isotype on peripheral immune cells, it has been hypothesized that this receptor mediates the immunosuppressive effects of cannabinoids. Unfortunately, there was a dearth of pharmacological studies with the endocannabinoids and human CB2 (hCB2). These studies compare and contrast the potency and efficacy of anandamide, 2-AG, and the synthetic cannabinoid HU210 at hCB2. Using [(35)S]guanosine-5'-O-(3-thio)triphosphate (GTPgammaS) and radioligand bindings in insect Sf9-hCB2 membranes, we showed that both endocannabinoids bound hCB2 with similar affinity and that the cannabinoids acted as full agonists in stimulating [(35)S]GTPgammaS exchange, although 2-AG was 3-fold more potent than anandamide (EC(50) = 38.9 +/- 3.1 and 121 +/- 29 nM, respectively). In a mammalian expression system (Chinese hamster ovary-hCB2 cells), HU210 and 2-AG maximally inhibited forskolin-stimulated cAMP synthesis (IC(50) = 1.61 +/- 0.42 nM and 1.30 +/- 0.37 microM, respectively) although anandamide was ineffective. In Chinese hamster ovary-hCB2 membranes, HU210 and 2-AG were also full agonists in stimulating [(35)S]GTPgammaS binding (EC(50) = 1.96 +/- 0.35 and 122 +/- 17 nM, respectively), but anandamide was a weak partial agonist (EC(50) = 261 +/- 91 nM; 34 +/- 4% of maximum). Due to its low intrinsic activity, coincubation with anandamide effectively attenuated the functional activity of 2-AG at hCB2. Collectively, the data showed that both endocannabinoids bound hCB2 with similar affinity, but only 2-AG functioned as a full agonist. Moreover, the agonistic activity of 2-AG was attenuated by anandamide. (+info)Are anandamide and cannabinoid receptors involved in ethanol tolerance? A review of the evidence. (6/954)
There have been significant developments towards the elucidation of molecular and cellular changes in neuronal second messenger pathways involved in the development of tolerance to and dependence on ethanol (EtOH). The long-term exposure to EtOH has been shown to affect several aspects of neuronal signal transduction as well as ligand-gated ion channels and receptor systems, including the receptors that are coupled to the superfamily of GTP binding regulatory proteins (G-proteins). The recent identification of a G-protein coupled receptor that was activated by delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, led to the discovery of endogenous agonists. One such agonist found to exist in mammalian brain was characterized to be an arachidonic acid (AA) metabolite and was named anandamide (AnNH). AnNH has been shown to bind specifically to the cannabinoid receptor (CB(1)) and mimic many of the pharmacological and behavioural effects of THC including tolerance development. The role of endocannabinoids and the CB(1) receptor signal transduction system in tolerance development to drugs of abuse has not been explored until recently. The findings presented in this review provide evidence for the first time that some of the pharmacological actions of EtOH including tolerance development may be mediated through participation of the endocannabinoid-CB(1) receptor signal transduction system. Recent studies have shown that chronic EtOH exposure produces downregulation of CB(1) receptors and an inhibition of CB(1) receptor agonist-stimulated GTPgammaS binding in mouse brain synaptic plasma membranes (SPM). The observed receptor downregulation results from the persistent stimulation of the receptors by the endogenous CB(1) receptor agonist AnNH, the synthesis of which is increased by chronic EtOH exposure. Further, the CB(1) receptor antagonist SR-141716A has been shown to block voluntary EtOH intake in rats and mice. Based on these studies, a hypothesis is presented to explain the possible involvement of the endocannabinoid system in the pharmacological and behavioural effects of EtOH. (+info)Down-regulation of anandamide hydrolase in mouse uterus by sex hormones. (7/954)
Endocannabinoids are an emerging class of lipid mediators, which mimic several effects of cannabinoids. Anandamide (arachidonoylethanolamide) is a major endocannabinoid, which has been shown to impair pregnancy and embryo development. The activity of anandamide is controlled by cellular uptake through a specific transporter and intracellular degradation by the enzyme anandamide hydrolase (fatty acid amide hydrolase, FAAH). We characterized FAAH in mouse uterus by radiochromatographic and immunochemical techniques, showing that the enzyme is confined to the epithelium and its activity decreases appreciably during pregnancy or pseudopregnancy because of lower gene expression at the translational level. Ovariectomy prevented the decrease in FAAH, and both progesterone and estrogen further reduced its basal levels, suggesting hormonal control of the enzyme. Anandamide was shown to induce programmed cell death in mouse blastocysts, through a pathway independent of type-1 cannabinoid receptor. Blastocysts, however, have a specific anandamide transporter and FAAH, which scavenge this lipid. Taken together, these results provide evidence of an interplay between endocannabinoids and sex hormones in pregnancy. These findings may also be relevant for human fertility, as epithelial cells from healthy human uterus showed FAAH activity and expression, which in adenocarcinoma cells was increased fivefold. (+info)Age dependent accumulation of N-acyl-ethanolamine phospholipids in ischemic rat brain. A (31)P NMR and enzyme activity study. (8/954)
N-acyl-ethanolamine phospholipids (NAPE) can be formed as a stress response during neuronal injury, and they are precursors for N-acyl-ethanolamines (NAE), some of which are endocannabinoids. The levels of NAPE accumulated during post-decapitative ischemia (6 h at 37 degrees C) were studied in rat brains of various age (1, 6, 12, 19, 30, and approximately 70 days) by the use of (31)P NMR spectroscopy of lipid extracts. This ability to accumulate NAPE was compared with the activity of N-acyltransferase and of NAPE-hydrolyzing phospholipase D (NAPE-PLD) in brain microsomes. These two enzymes are involved in the formation and degradation of NAPE, respectively. The results showed that 1) the ability to accumulate NAPE during post-decapitative ischemia is especially high in the youngest rats and is markedly reduced in older brains [in 1-day-old rat brains NAPE accumulated to 1.5% of total phospholipids, while in 30-day-old rat brains NAPE accumulation could not be detected (detection limit 0.09%)] and 2) this age pattern of accumulation can be explained by a combination of the decreased activity of N-acyltransferase and the increased activity of NAPE-PLD during development. These results point out that it would be advantageous to investigate a potential cytoprotective role of NAPE in the brains of very young rats. (+info)
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- Google Patents
Frontiers | Cannabinoids Modulate Neuronal Activity and Cancer by CB1 and CB2 Receptor-Independent Mechanisms | Pharmacology
AntagonistsEthanolEndocannabinoidsAgonistAgonistsCannabisPharmacologyCompoundsNegative allosteric modulatorsAllosteric modulators of cannabinoid CB1 receptorAnandamideAffinityEnzymesSynthetic cannabinoidsNeurotransmitterPsychoactivePhysiological2017Positive allosteric modulatorPeripheral cannabinoidEndogenous cannabinoidOpioid and cannabinoid receptorsTypes of cannabinoidsSignalingModulationExpression of cannabinoid receptorsBindsNeuropathic painMetabolismLigandMarijuanaTherapeutic potentialType 1 cannabinoidBind to cannabinoidModulateKnockout miceLipidsSelectivelyPathwaysGPR55MoleculesEfficacyTowards cannabinoidMechanisms of cannabinoidCompoundCharacterizationTherapeuticsInhibitorsTransmembraneInteract
Antagonists1
- Superfusion of the cannabinoid receptor (CB1) agonist WIN55212-2 (WIN2) onto CeA neurons decreased evoked GABA(A) receptor-mediated inhibitory postsynaptic potentials (IPSPs) in a concentration-dependent manner, an effect prevented by the CB1 antagonists Rimonabant (SR141716, SR1) and AM251. (scripps.edu)
Ethanol1
- We used a slice preparation to investigate the physiological role of cannabinoids and their interaction with ethanol on inhibitory synaptic transmission in CeA. (scripps.edu)
Endocannabinoids16
- The CB 1 receptor is activated by cannabinoids , generated naturally inside the body ( endocannabinoids ) or introduced into the body as cannabis or a related synthetic compound. (wikipedia.org)
- Endocannabinoids are essential modulators of synaptic transmission throughout the CNS. (jneurosci.org)
- Following release from postsynaptic neurons, endocannabinoids travel through the synaptic cleft to engage presynaptic cannabinoid CB 1 receptors. (jneurosci.org)
- The chemical definition encompasses a variety of distinct chemical classes: the classical cannabinoids structurally related to THC, the nonclassical cannabinoids, the aminoalkylindoles , the eicosanoids related to the endocannabinoids, 1,5-diarylpyrazoles , quinolines and arylsulphonamides and additional compounds that do not fall into these standard classes but bind to cannabinoid receptors. (wikidoc.org)
- Plant-derived cannabinoids and their derivatives exert a wide variety of biological effects by mimicking endogenous compounds (endocannabinoids), which primarily activate two cannabinoid-specific G-protein-coupled receptors, CB1 and CB2, encoded by the Cnr1 and Cnr2 genes, respectively. (aacrjournals.org)
- Endocannabinoids are synthesized "on demand" from membrane phospholipids in response to increases in intracellular calcium (as occurs with neuronal activation or cell stress) and immediately released to act in paracrine fashion on nearby G i/o -protein coupled receptors CB 1 R 1 and CB 2 R. Endocannabinoids are then rapidly cleared by cellular uptake and enzymatic degradation. (aspetjournals.org)
- In addition to increasing levels of endocannabinoids, the system often responds to stress by altering the expression of CB 1 R and/or CB 2 R. In some diseases, such as neuropathic pain and multiple sclerosis, increases in cannabinoid receptor expression are thought to reduce symptoms and/or inhibit progression of disease and thus serve a protective role (for review, see Pertwee, 2009 ). (aspetjournals.org)
- The discovery of endocannabinoids as pain modulators has opened new mechanistic perspectives [ 1 ]. (mdpi.com)
- Many disease-ameliorating effects of cannabinoids-endocannabinoids are receptor mediated, but many are not, indicating non-CBR signaling pathways. (unboundmedicine.com)
- Cannabinoids-endocannabinoids are anti-inflammatory, anti-proliferative, anti-invasive, anti-metastatic and pro-apoptotic in most cancers, in vitro and in vivo in animals. (unboundmedicine.com)
- Similarities between effects of cannabinoids-endocannabinoids, omega-3 LCPUFA and CLAs/CLnAs as anti-inflammatory, antiangiogenic, anti-invasive anti-cancer agents indicate common signaling pathways. (unboundmedicine.com)
- TY - JOUR T1 - Cannabinoids and omega-3/6 endocannabinoids as cell death and anticancer modulators. (unboundmedicine.com)
- Endocannabinoids play their main roles by targeting both cannabinoid and other membrane and nuclear receptors. (els.net)
- The binding of endocannabinoids to cannabinoid, vanilloid and peroxisome proliferator‐activated receptors triggers several signal transduction pathways. (els.net)
- RVDPVNFKLLSH) is the major peptide of a family of endogenous peptide endocannabinoids (pepcans) shown to act as negative allosteric modulators (NAM) of cannabinoid CB1 receptors. (siliconinvestor.com)
- There is evidence that besides the two cannabinoid receptor subtypes cloned so far, additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of endocannabinoids that include, for example, motor coordination, memory procession, pain modulation and neuroprotection. (cannabis-med.org)
Agonist29
- The primary endogenous agonist of the human CB 1 receptor is anandamide . (wikipedia.org)
- MN-25 (UR-12) is a drug invented by Bristol-Myers Squibb, that acts as a reasonably selective agonist of peripheral cannabinoid receptors. (wikipedia.org)
- In addition, the proposal seeks to assess whether the cannabinoid agonist dronabinol, when given to patients with SCZ and CUD, will also ameliorate this BRC deficit, and, thus, whether dronabinol could be considered as a potential adjunctive treatment (given with an antipsychotic medication) to decrease their cannabis use. (clinicaltrials.gov)
- In mu opioid receptor binding studies on rat cerebral cortex membrane homogenates, the agonist 3 H-DAMGO bound to a homogeneous class of binding sites with a K D of 0.68±0.02 nM and a B max of 203±7 fmol/mg protein. (springer.com)
- This article is about the cannabinoid agonist. (rug.nl)
- AM-679 (part of the AM cannabinoid series ) is a drug that acts as a moderately potent agonist for the cannabinoid receptors , with a K i of 13.5 nM at CB 1 and 49.5 nM at CB 2 . (rug.nl)
- To assess involvement of CB 1 receptors in the reinforcing effects of 2-AG, we pretreated monkeys with the cannabinoid CB 1 receptor inverse agonist/antagonist rimonabant [ N -piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide]. (jneurosci.org)
- The CB 1 -specific agonist ACEA had no effect, whereas the CB 2 antagonist AM630 blocked the effect of the natural cannabinoid tetrahydrocannabivarin, confirming mediation via the CB 2 receptor. (springer.com)
- The present invention provides a simple and improved dose form that is capable of providing a controlled release of GABA.sub.B receptor agonist contained in. (patents.com)
- The reason for the excitement appears to be an Oct. 19 press release detailing positive midstage results for its lead drug ralinepag, an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension (PAH). (fool.com)
- Arena's S1P receptor modulator Etrasimod, and cannabinoid receptor-2 agonist APD371, may also hold promise. (fool.com)
- In diseases for which cannabinoid receptors are protective, knowledge of the mechanisms of receptor up-regulation could be used to design therapies to regionally increase receptor expression and thus increase efficacy of an agonist. (aspetjournals.org)
- I farmakologi er en allosterisk modulator ( allo - fra den græske betydning "anden") et stof , som indirekte påvirker virkningerne af en agonist eller omvendt agonist ved et mål protein , for eksempel en receptor . (wikipedia.org)
- En positiv allosterisk modulator (PAM) eller allosterisk forstærker inducerer en amplifikation af den orthosteriske agonists virkning enten ved at forøge bindings-affiniteten eller den funktionelle effekt af den orthosteriske agonist for målproteinet. (wikipedia.org)
- En negativ-sidet allosterisk modulator har en negativ effekt på styrken, men en positiv effekt på effekten af en agonist. (wikipedia.org)
- CB1 Receptor Allosteric Modulators Display both Agonist and Signaling Pathway Specificity. (utoronto.ca)
- Lasofoxifene mediates an agonist effect on estrogen receptors expressed on bone to mimic the positive effects of estrogen to reduce the production and lifespan of osteoclasts via altering the NF-kappaB ligand (RANKL)/RANK/osteoprotegerin system, stimulation of osteoblast (the bone forming cells) activity and additional effects on calcium homeostasis [ 4 ] . (drugbank.ca)
- A study also suggests that lasofoxifene may also act as an inverse agonist at CB2 cannabinoid receptor which is expressed in bone to inhibit osteoclast formation and resorptive activity. (drugbank.ca)
- The primary psychoactive component of Cannabis, delta 9-tetrahydrocannabinol (Δ9-THC), demonstrates its effects through weak partial agonist activity at Cannabinoid-1 (CB1R) and Cannabinoid-2 (CB2R) receptors. (drugbank.ca)
- In contrast to THC's weak agonist activity, CBD has been shown to act as a negative allosteric modulator of the cannabinoid CB1 receptor, the most abundant G-Protein Coupled Receptor (GPCR) in the body 2 . (drugbank.ca)
- Allosteric regulation is achieved through the modulation of receptor activity on a functionally distinct site from the agonist or antagonist binding site. (drugbank.ca)
- Arena was granted US Patent No. 8,778,950, entitled "Cannabinoid Receptor Modulators," by the United States Patent and Trademark Office for APD371, an agonist of the cannabinoid receptor 2 (CB2). (bio-medicine.org)
- The inverse agonist MK-9470 makes it possible to produce in vivo images of the distribution of CB 1 receptors in the human brain with positron emission tomography . (wikidoc.org)
- Pubmed ID: 19861403 We investigated whether the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS, 20 microg/side) microinfused into the basolateral amygdala (BLA) would reverse stress-induced impairment of extinction in two aversive learning paradigms: contextual fear conditioning and conditioned taste aversion (CTA). (jove.com)
- THC (D9-tetrahydrocannabinol), the main source of the pharmacological effects caused by the use of cannabis including the medicinal benefits of the plant, is an agonist to both the CB1 and the CB2 subtype of these receptors. (cannabis-med.org)
- An agonist is a chemical that promotes a biological response by binding to a receptor. (cbdoilanxietyshop.com)
- An antagonist is a type of receptor ligand or drug that blocks or dampens a biological response by binding to and blocking a receptor rather than activating it like an agonist. (cbdoilanxietyshop.com)
- An inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. (cbdoilanxietyshop.com)
- A neutral antagonist has no activity in the absence of an agonist or inverse agonist but can block the activity of either by competing at the receptor site. (cbdoilanxietyshop.com)
Agonists9
- This is because CB1 receptor agonists block off or "deactivate" the receptor. (medicalnewstoday.com)
- Classical cannabinoid agonists (structures shown in Table 1 ) bind to and activate cannabinoid receptors 1 and 2 (CB1, CB2) that modulate signal transduction cascades to produce various physiological and pathological outcomes. (frontiersin.org)
- Selective Estrogen Receptor Modulators: Cannabinoid Receptor Inverse Agonists with Differential CB1 and CB2 Selectivity. (adooq.com)
- Repeated administration of receptor agonists may result in receptor internalization and/ or a reduction in receptor protein signalling. (wikidoc.org)
- The development of cannabinoid CBII receptor agonists for the treatment of central neuropathies. (neuropathie.nu)
- At doses exceeding the psychotropic threshold, ingestion of exogenous CB1 receptor agonists or cannabis, respectively, usually causes an enhanced well-being and relaxation with an intensification of ordinary sensory experiences. (cannabis-med.org)
- Allosteric modulators can, however, change the way agonists interact with the receptor site. (cbdoilanxietyshop.com)
- CB1 receptor agonists are responsible for cannabis's psychoactive effects, as well as increasing hunger or sleepiness. (cbdoilanxietyshop.com)
- C6 rat astroglioma cells were challenged with 1 μg/ml Aβ 1-42 in the presence or absence of selective agonists and antagonists of cannabinoid (CB)1 and CB2 receptors. (420magazine.com)
Cannabis28
- The mechanism of action of cannabidiol, one of the major constituents of cannabis, is not well understood but a noncompetitive interaction with mu opioid receptors has been suggested on the basis of saturation binding experiments. (springer.com)
- another major constituent of cannabis) and rimonabant (a cannabinoid CB 1 receptor antagonist) were studied. (springer.com)
- Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. (nih.gov)
- CBD is one of the compounds called cannabinoids in the cannabis plant. (medicalnewstoday.com)
- Cannabinoids include the active constituents of Cannabis or are molecules that mimic the structure and/or function of these Cannabis -derived molecules. (frontiersin.org)
- Cannabinoid receptors were originally discovered as being sensitive to Δ 9 - tetrahydrocannabinol (Δ 9 -THC, commonly called THC), which is the primary psychoactive cannabinoid found in cannabis . (wikidoc.org)
- Cannabinoids are a group of terpeno phenolic compounds present in Cannabis ( Cannabis sativa L). The broader definition of cannabinoids refer to a group of substances that are structurally related to tetrahydrocannabinol (THC) or that bind to cannabinoid receptors . (wikidoc.org)
- The term cannabinoids also refers to a unique group of secondary metabolites found in the cannabis plant, which are responsible for the plant's peculiar pharmacological effects. (wikidoc.org)
- CB1 receptors appear to be responsible for the euphoric and anticonvulsive effects of cannabis. (wikidoc.org)
- CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis. (wikidoc.org)
- Natural cannabinoids are only known to occur naturally in the cannabis plant, and are concentrated in a viscous resin that is produced in glandular structures known as trichomes . (wikidoc.org)
- In addition to cannabinoids, the resin is rich in terpenes , which are largely responsible for the odour of the cannabis plant. (wikidoc.org)
- Most of the biological effects of cannabis are due to the activation of specific cannabinoid receptors. (nottingham.ac.uk)
- The cannabinoid molecules are derived from Cannabis sativa plant which acts on the cannabinoid receptors types 1 and 2 (CB 1 and CB 2 ) which have been explored as potential therapeutic targets for drug discovery and development. (hindawi.com)
- Panlilio LV, Justinova Z. Preclinical Studies of Cannabinoid Reward, Treatments for Cannabis Use Disorder, and Addiction-Related Effects of Cannabinoid Exposure . (ucsd.edu)
- Her research is directed both toward gaining insight into the deleterious effects of cannabis smoking, the potential for cannabis a medicine and the development of small molecules targeting G protein coupled receptors. (utoronto.ca)
- Cannabinoids, drugs that share the same target as Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. (pubmedcentralcanada.ca)
- From a pharmacological perspective, Cannabis' diverse receptor profile explains its potential application for such a wide variety of medical conditions. (drugbank.ca)
- Cannabis contains more than 400 different chemical compounds, of which 61 are considered cannabinoids, a class of compounds that act upon cannabinoid receptors of the body [A (drugbank.ca)
- Cannabinoids, the biologically active constituents of marijuana ( Cannabis sativa ), produce a wide spectrum of central and peripheral effects, such as alterations in cognition and memory, analgesia, anticonvulsion, anti-inflammation, and alleviation of both intraocular pressure and pain relief ( 1 ). (aacrjournals.org)
- MRes projects might include investigation of novel allosteric modulators of µ-opioid receptors, investigation of how the non-psychoactive constituents of cannabis affect cannabinoid receptor signalling as well as how endogenous cannabinoid-like molecules modulate calcium and TRP channel signalling. (edu.au)
- He is also the first author of a new volume in the series titled The Analytical Chemistry of Cannabis: Quality Assessment, Assurance, and Regulation of Medicinal Marijuana and Cannabinoid Preparations . (rti.org)
- While cannabis may contain many cannabinoid (tricyclic dibenzopyran) compounds, the psychoactive effects are mediated by Δ9 Tetrahydrocannabinol (THC). (omicsonline.org)
- The effects of cannabis are primarily exerted through the cannabinoid receptors, CB1 and CB2. (omicsonline.org)
- Some receptors respond to chemicals in cannabis called cannabinoids, often in similar ways to prescribed medications but in a more natural, healthier and sometimes even more powerful way. (cbdoilanxietyshop.com)
- Cannabis affects ECS receptors because cannabis contains cannabinoids, similar to the cannabinoids our bodies produce naturally. (cbdoilanxietyshop.com)
- Less than 20 years ago the ?eld of cannabis and the cannabinoids was still c- sidered a minor, somewhat quaint, area of research. (springer.com)
- These new drugs try to take advantage of the receptors that bind the active chemical in hemp (cannabis), the plant from which marijuana is derived. (dana.org)
Pharmacology3
- Pertwee RG (2006) Cannabinoid pharmacology: the first 66 years. (springer.com)
- Ruth Ross is engaged in research into the molecular pharmacology of the cannabinoids and related lipid signalling systems. (utoronto.ca)
- Thanks to early findings published in the British Journal of Pharmacology some terpenes have been identified as having allosteric modulator properties, capable of slowing down neurotransmitter signaling. (scriphessco.com)
Compounds21
- In this work, we explored the molecular framework of the known CB1R allosteric modulator PSNCBAM-1 with the aim to generate new bioactive analogs and to deepen the structure-activity relationships of this type of compounds. (nih.gov)
- Claimed compounds have modulation effect on CB cannabinoid receptor. (russianpatents.com)
- Also invention concerns application of the compounds in obtaining pharmaceutical composition, pharmaceutical composition with modulation effect on CB cannabinoid receptor, and compound of the general formula (IV) with radical values as indicated in the claim. (russianpatents.com)
- Compounds that interact with and stimulate the activity of CANNABINOID RECEPTORS. (nih.gov)
- Compounds that inhibit or block the activity of CANNABINOID RECEPTORS. (nih.gov)
- Compounds and drugs that inhibit or block the activity of CCR5 RECEPTORS. (nih.gov)
- Allosteric modulators of cannabinoid receptor 1: developing compounds for improved specificity. (nih.gov)
- This system responds to different compounds in the body through two cannabinoid (CB) receptors, called the CB1 and CB2 receptors. (medicalnewstoday.com)
- Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. (patents.com)
- Hydrazone compounds which modulate cannabinoid receptors are presented. (patents.com)
- Both compounds bind to the cannabinoid receptors in the brain. (wikidoc.org)
- and synthetic cannabinoids are similar compounds produced in a laboratory. (wikidoc.org)
- In order to ascertain whether the test compounds had affinity for the CB2 receptor, a radioligand binding assay was developed using porcine spleen membranes. (nottingham.ac.uk)
- However, when the test compounds were assessed in this assay system, no affinity for the CB2 receptor was observed. (nottingham.ac.uk)
- Our results illustrate an unbiased and translational drug discovery strategy for ideal psychoactive compounds and identified selective appetite modulators in two vertebrate species. (sciencemag.org)
- These findings expand our knowledge about cell type-specific differential neuronal cannabinoid receptor signaling and suggest CB(2)R-selective compounds as potential therapeutic approaches. (mdc-berlin.de)
- Its acid metabolite THC-COOH (11-nor-9-carboxy-THC), the non-psychotropic cannabidiol (CBD), analogues of these natural compounds, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. (cannabis-med.org)
- Cannabimimetics (commonly referred to as synthetic cannabinoids), a group of compounds encompassing a wide range of chemical structures, have been developed by scientists in order to achieve selectivity toward one or both receptors for improved therapeutic activity with reduced adverse effects. (omicsonline.org)
- The cannabinoids are a group of compounds that either structurally is related to Δ 9 -Tetrahydrocannabinol (Δ 9 -THC) or that which bind to cannabinoid receptors. (omicsonline.org)
- The ability of these compounds to achieve this effect is influenced by selectivity of receptor as well as route of administration and metabolism [ 1 - 3 ]. (omicsonline.org)
- The data support the assumption that compounds able to selectively block CB2 receptors may have therapeutic potential in controlling Aβ-related pathology, due to their beneficial effects devoid of psychotropic consequences. (420magazine.com)
Negative allosteric modulators4
- SN15b and the biphenyl-urea analog SC4a significantly inhibited the response produced by CP55,940 in the low µM range, thus behaving as negative allosteric modulators (NAMs). (nih.gov)
- 2016). Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators. (utoronto.ca)
- Ligand-Biased and Probe-Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators. (discoverx.com)
- Bernat V, Brox R, Heinrich MR, Auberson YP, Tschammer N. Ligand-Biased and Probe-Dependent Modulation of Chemokine Receptor CXCR3 Signaling by Negative Allosteric Modulators. (discoverx.com)
Allosteric modulators of cannabinoid CB1 receptor1
- Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor. (nih.gov)
Anandamide8
- Bisogno T, Hanuš L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V (2001) Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. (springer.com)
- Also, 2-AG selectively binds to cannabinoid receptors, while anandamide also interacts with noncannabinoid binding sites such as vanilloid receptors (for review, see Pertwee, 2008 ). (jneurosci.org)
- Ross RA (2003) Anandamide and vanilloid TRPV1 receptors. (springer.com)
- Anandamide , also known as N -arachidonoylethanolamine or AEA , is an endogenous cannabinoid neurotransmitter . (wikidoc.org)
- The discovery of anandamide came from research into CB1 and CB2, as it was inevitable that a naturally occurring (endogenous) chemical would be found to affect these receptors. (wikidoc.org)
- Moreover, anandamide is thought to be an endogenous ligand for vanilloid receptors (which are involved in the transduction of acute and inflammatory pain signals), activating the receptor in a PKC-dependent (protein kinase C-dependent) manner. (wikidoc.org)
- 12. Facci L, Dal Toso R, Romanello S, Buriani A, Skaper SD, Leon A. Mast cells express a peripheral cannabinoid receptor with differentia] sensitivity to anandamide and palmitoylethanolamide. (pubmedcentralcanada.ca)
- Moreover, Aβ provoked down-regulation of CB1 receptors together with a reduction of anandamide concentration, whereas CB2 receptors were up-regulated and 2-arachidonoyl glycerol concentration was increased. (420magazine.com)
Affinity8
- In particular, the introduction of a NH group between the pyridine ring and the phenyl nucleus generated the amino-phenyl-urea derivative SN15b that behaved as a positive allosteric modulator (PAM), increasing the CB1R binding affinity of the orthosteric ligand CP55,940. (nih.gov)
- It has moderate affinity for CB2 receptors with a Ki of 11 nM, but 22x lower affinity for the psychoactive CB1 receptors with a Ki of 245 nM. (wikipedia.org)
- The structure and pharmacological activity of AB-005 was published in 2010, prior to its commercial availability in 2012, where it was reported to have high affinity for both CB1 ( K i = 5.5 nM) and CB2 receptors ( K i = 0.48 nM). (rug.nl)
- THC has approximately equal affinity for the CB1 and CB2 receptors. (wikidoc.org)
- Affinity for the CB1 receptor was assessed using radioligand binding assays in rat brain membranes. (nottingham.ac.uk)
- Lasofoxifene is a non-steroidal 3rd generation selective estrogen receptor modulator (SERM) that selectively binds to both ERα and ERβ with high affinity. (drugbank.ca)
- Description: Binding affinity for recombinant human CB 2 receptors expressed in COS cells, displacing [ 3 H]-CP-55,940. (guidetopharmacology.org)
- NAGly is believed to activate the cannabinoid receptor GPR18 with no affinity for cannabinoid receptor (CB) 1 [ 1 , 2 , 3 ] and transient receptor potential vanilloid 1 (TRPV1) [ 1 ]. (mdpi.com)
Enzymes2
- The endogenous network of AEA and 2‐AG metabolic enzymes and their main receptors. (els.net)
- The ECS is made up of cannabinoid receptors, cannabinoids and enzymes which work together to keep our bodies in balance, alongside other receptors in our bodies. (cbdoilanxietyshop.com)
Synthetic cannabinoids2
- AB-005 features groups found in other previously reported synthetic cannabinoids: the tetramethylcyclopropane group of UR-144 and XLR-11 as well as the (1-methyl-2-piperidinyl)methyl substituent of AM-1248 and AM-1220 . (rug.nl)
- and synthetic cannabinoids generated in a laboratory. (omicsonline.org)
Neurotransmitter4
- The CB 1 receptor is a pre-synaptic heteroreceptor that modulates neurotransmitter release when activated in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. (wikipedia.org)
- A reuptake modulator , or transporter modulator , is a type of drug which modulates the reuptake of one or more neurotransmitters via their respective neurotransmitter transporters . (wikipedia.org)
- Cannabinoid- and LPI-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. (utoronto.ca)
- 2017) and other neurotransmitter receptors (Laun et al. (ukessays.com)
Psychoactive5
- THC (the psychoactive cannabinoid in maruajana) has active effects, and CBD (the largely non-active in hemp) likely acts by simply directly or indirectly 'blocking' receptors. (her2support.org)
- This is the receptor that marijuana's primary psychoactive ingredient tetrahydrocannabinol (THC) targets to alleviate pain. (medicalnewstoday.com)
- Receptor-Positive Allosteric Modulator Reduces Neuropathic Pain in the Mouse with No Psychoactive Effects. (utoronto.ca)
- This latest research from Halifax, Canada has found that CBD is a negative allosteric modulator of the cannabinoid receptor 1 (CB 1 ), the same receptor responsible for THC's psychoactive high . (hightimes.com)
- The cannabinoid delta-9-tetrahydrocannabinol is the principal psychoactive ingredient of marijuana. (antikoerper-online.de)
Physiological5
- Before the 1980's, it was often speculated that cannabinoids produced their physiological and behavioral effects via nonspecific interaction with cell membranes, instead of interacting with specific membrane-bound receptors . (wikidoc.org)
- 6 In order to explore the physiological consequences of this interaction, we examined the effect of receptor activation on the extent of Src and STAT3 phosphorylation and neuritogenesis in Neuro‐2A cells. (deepdyve.com)
- Cannabinoid receptors work through a variety of signaling mechanisms to exert physiological and pathophysiological effects in different tissues. (aspetjournals.org)
- While both CBD and THC are used for medicinal purposes, they have different receptor activity, function, and physiological effects. (drugbank.ca)
- This emerging class of drugs is the first fruit of a burgeoning research sector aimed at understanding the many actions of endogenous cannabinoids, naturally occurring chemicals that serve physiological purposes. (dana.org)
20172
- 2017) (‐)‐β‐Caryophyllene, a CB2 receptor‐selective phytocannabinoid, suppresses motor paralysis and neuroinflammation in a murine model of multiple sclerosis. (els.net)
- 2017) Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B. International Journal of Infectious Diseases 59: 124-130. (els.net)
Positive allosteric modulator2
- Pepcan-12 (RVD-hemopressin) is a CB2 receptor positive allosteric modulator constitutively secreted by adrenals and in liver upon tissue damage. (siliconinvestor.com)
- Here, it is shown that pepcan-12 acts as a potent (K i value ~50?nM) hCB2 receptor positive allosteric modulator (PAM). (siliconinvestor.com)
Peripheral cannabinoid1
- The pyrazole caboxamide SR144528 is a selective antagonist at the peripheral cannabinoid CB2 receptor. (drugabuse.gov)
Endogenous cannabinoid3
- These results indicate that the endogenous cannabinoid system may represent a potential therapeutic target for prevention or treatment of colorectal cancer. (aacrjournals.org)
- Alterations in the endogenous cannabinoid system have been described in almost every category of disease. (aspetjournals.org)
- A new weight-loss drug illustrates both the promise and problem with tackling cravings, such as for food or nicotine, via the brain's endogenous cannabinoid system. (dana.org)
Opioid and cannabinoid receptors2
- 2 In order to investigate interactions between opioid and cannabinoid receptors, we epitope tagged μ, δ and κ opioid receptors with Renilla luciferase and CB1 cannabinoid or CCR5 chemokine receptors with yellow fluorescent protein and examined the extent of substrate hydrolysis induced bioluminescence resonance energy transfer (BRET) signal. (deepdyve.com)
- We have particular interests in ligand biased signalling, allosteric modulation of receptor signalling and signalling at polymorphic variants of human opioid and cannabinoid receptors. (edu.au)
Types of cannabinoids2
- synthetic and other types of cannabinoids (many developed seeking modulators of other signaling systems, but found to interact with the classic CB1 and/or CB2 receptors). (frontiersin.org)
- Tetrahydrocannabinol (THC) and cannabidiol (CBD) are two types of cannabinoids found naturally in the resin of the marijuana plant, both of which interact with the cannabinoid receptors found in the human body. (drugbank.ca)
Signaling8
- 4 In order to examine the implications of these interactions to signaling, we used GTPγS binding and mitogen‐activated protein kinase (MAPK) phosphorylation assays and examined the effect of receptor activation on signaling. (deepdyve.com)
- These advances have provided researchers the basic tools to interrogate critical but diverse aspects of GPCR signaling, such as receptor conformation, receptor-effector specificity and the role of receptor subcellular distribution, in signaling efficacy. (keystonesymposia.org)
- Allosteric Modulation of a Cannabinoid G Protein-Coupled Receptor: Binding Site Elucidation and Relationship to G Protein Signaling. (utoronto.ca)
- Biased and constitutive signaling in the CC-chemokine receptor CCR5 by manipulating the interface between transmembrane helices 6 and 7. (discoverx.com)
- Steen A, Thiele S, Guo D, Hansen LS, Frimurer TM and Rosenkilde MM. Biased and constitutive signaling in the CC-chemokine receptor CCR5 by manipulating the interface between transmembrane helices 6 and 7. (discoverx.com)
- β-Arrestin recruitment and G protein signaling by the atypical human chemokine decoy receptor CCX-CKR. (discoverx.com)
- The results suggest that cannabinoid signaling differentially affects memory in a task-, region-, and memory stage-dependent manner. (jove.com)
- 2016) Mechanisms of biased β‐arrestin‐mediated signaling downstream from the cannabinoid 1. (els.net)
Modulation5
- Lynn AB, Herkenham M (1994) Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. (springer.com)
- The impact and consequences of cannabinoid modulation of monoaminergic (dopamine, norepinephrine, and serotonin) circuits is becoming more clear. (buecher.de)
- In addition, the impact and consequences of cannabinoid modulation of monoaminergic circuits is steadily emerging demonstrating a significant interaction between these two systems in a variety of psychiatric (affective disorders) and neurological disorders (multiple sclerosis, pain). (worldcat.org)
- Modulation of L-α-lysophosphatidylinositol /GPR55 MAP kinase signalling by cannabinoids. (utoronto.ca)
- Allosteric Modulation of the Cannabinoid CB1 Receptor. (utoronto.ca)
Expression of cannabinoid receptors1
- However, little is known about the expression of cannabinoid receptors in CRC. (aacrjournals.org)
Binds3
- A receptor modulator , or receptor ligand , is a type of drug which binds to and modulates receptors . (wikipedia.org)
- When THC binds to a CB 1 receptor on the outside of a neuron, the receptor creates certain signals on the inside of the cell. (hightimes.com)
- If CBD binds to the CB 1 receptor at the same time as THC, the neuron gets a lesser signal . (hightimes.com)
Neuropathic pain4
- Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. (pubmedcentralcanada.ca)
- Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. (pubmedcentralcanada.ca)
- Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. (pubmedcentralcanada.ca)
- Since 1994 when Meller and colleagues for the first time demonstrated that by inhibiting astrocyte functions, neuropathic pain did not emerge, many glia modulators have been explored as new inroads in the treatment of neuropathic pain. (neuropathie.nu)
Metabolism2
- Cannabinoid receptor type-1 (CB1) plays a crucial role in controlling energy metabolism through central and peripheral mechanisms. (jci.org)
- Cannabinoid receptor type-1 (CB1) is known to have a substantial impact on the regulation of energy metabolism via central and peripheral mechanisms. (jci.org)
Ligand5
- Contreras PC, Tam L, Drower E, Rafferty MF (1993) [3H]naltrindole: a potent and selective ligand for labeling delta-opioid receptors. (springer.com)
- The activation of the CB 1 and CB 2 receptors causes the numerous intracellular effects which may be cell type and ligand specific and involve the inhibition of various voltage gated Ca +2 channels and adenylate cyclase activity and the activation of K + channels, resulting in lower levels of cAMP along with activation of MAPK pathways [ 5 ]. (hindawi.com)
- En negativ modulator (NAM) reducerer virkningerne af den orthosteriske ligand , men er inaktiv i fravær af den orthosteriske ligand. (wikipedia.org)
- De er i stand til at binde målproteinet og udøve deres virkning i fravær af en orthosterisk ligand, medens tilstedeværelsen af en orthosterisk ligand typisk kræves for at observere de indirekte virkninger af rene allosteriske modulatorer. (wikipedia.org)
- Given NAGly mediated actions we speculate that GPR18 and its ligand NAGly are modulators of glial and neuronal cells during neuronal damage. (mdpi.com)
Marijuana2
- Elsohly MA, Slade D (2005) Chemical constituents of marijuana: the complex mixture of natural cannabinoids. (springer.com)
- Marijuana smoke produces its psychotropic effects by delivering milligram quantities of cannabinoids, including primarily Δ-9-tetrahydrocannabinol (THC), 3 to the lung ( 1 ). (jimmunol.org)
Therapeutic potential1
- Allosteric modulators of CB 1 offer one new approach that has tremendous therapeutic potential. (aspetjournals.org)
Type 1 cannabinoid4
- Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors. (pubmedcentralcanada.ca)
- Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo. (unboundmedicine.com)
- Van Laere K et al: "Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo. (unboundmedicine.com)
- TY - JOUR T1 - Regional changes in type 1 cannabinoid receptor availability in Parkinson's disease in vivo. (unboundmedicine.com)
Bind to cannabinoid2
- 2-AG and AEA both bind to cannabinoid 1 receptor (CB 1 ) and cannabinoid 2 receptor (CB 2 ). (hindawi.com)
- We know that cannabinoids like THC tend to bind to cannabinoid receptors 1 and 2 (CB1 & CB2). (cbdoilanxietyshop.com)
Modulate3
- Recently, the cannabinoid receptors CB 1 and CB 2 were shown to modulate bone formation and resorption in vivo , although little is known of the mechanisms underlying this. (springer.com)
- The CNS represents a well-studied area and cancer is emerging in terms of understanding mechanisms by which cannabinoids modulate their activity. (frontiersin.org)
- Cannabinoids modulate fibrogenesis in systemic sclerosis (SSc, scleroderma) [ 6 - 8 ], thus are attractive as possible therapeutic agents for treatment of this condition. (omicsonline.org)
Knockout mice1
- Additionally, using cannabinoid receptor knockout mice, we found that SSI was still intact in CB(1)R-deficient but abolished in CB(2)R-deficient mice. (mdc-berlin.de)
Lipids1
- Natural cannabinoids, also called herbal cannabinoids and classical cannabinoids , are nearly insoluble in water but soluble in lipids , alcohols , and other non-polar organic solvents . (wikidoc.org)
Selectively2
- Since this receptor is implicated in several maladies, such as obesity, pain, and neurodegenerative disorders, there is interest in developing therapeutics that selectively target this receptor. (aspetjournals.org)
- Benito C, Nunez E, Tolon RM, Carrier EJ, Rabano A, Hillard CJ, Romero J (2003) Cannabinoid CB 2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer's disease brains. (springer.com)
Pathways2
- More recently, we reported that the immunosuppressive property of THC can be attributed, at least in part, to its ability to induce apoptosis in T cells and dendritic cells through ligation of CB2 receptors and that the latter was regulated by activation of nuclear factor-κB ( 8 ), recruiting both intrinsic and extrinsic pathways of apoptosis. (aacrjournals.org)
- In this article, we will review the metabolic pathways of eCBs, and the latest advances on their potential receptor targets. (els.net)
GPR553
- Brown A, Wise A (2005) Identification of modulators of GPR55 activity. (springer.com)
- The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. (utoronto.ca)
- 2014) Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. (els.net)
Molecules4
- Small organic molecules that act as allosteric activators of the calcium sensing receptor (CaSR) in the PARATHYROID GLANDS and other tissues. (nih.gov)
- CBD does not deactivate CB1 receptors but may influence other molecules to block them off. (medicalnewstoday.com)
- Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. (hindawi.com)
- GPRs are a large group of evolutionary related proteins that have cell surface receptors that detect molecules outside the cell and activate cellular responses. (cbdoilanxietyshop.com)
Efficacy1
- Obtaining a comprehensive understanding of the diverse mechanisms of cannabinoid action may lead to the design and development of therapeutic agents with greater efficacy and specificity for their cellular targets. (frontiersin.org)
Towards cannabinoid1
- 2018). Research has shown that when CBD and THC are consumed at the same time, CBD is an indirect antagonist towards cannabinoid receptor type 1 (CB1) and cannabinoid receptor type 2 (CB2). (ukessays.com)
Mechanisms of cannabinoid1
- Here we review current findings on the mechanisms of cannabinoid receptor regulation in disease and discuss their therapeutic implications. (aspetjournals.org)
Compound2
- Compound SC4a , SN15b , SC33 and FG45a were incubated at different concentrations with membrane preparations obtained from CHO-K1 cells overexpressing h CB2 receptors in presence of 0.5 nM of [ 3 H]CP55,940. (nih.gov)
- The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof which has the effect of antagonizing the LPA1 receptor. (sumobrain.com)
Characterization1
- Munro S, Thomas KL, Abu-Shaar M (1993) Molecular characterization of a peripheral receptor for cannabinoids. (springer.com)
Therapeutics1
- In both cases, regulation of cannabinoid receptor expression is of interest from a therapeutics perspective. (aspetjournals.org)
Inhibitors1
- Examples of reuptake modulators include reuptake inhibitors (transporter blockers) and reuptake enhancers . (wikipedia.org)
Transmembrane1
- GPR18 is a seven-transmembrane G-protein coupled receptor consisting of 331 amino acids. (mdpi.com)
Interact2
- Cannabidiol (CBD) has been found to interact with a variety of different biological targets, including cannabinoid receptors (Pisanti et al. (ukessays.com)
- However, it remains unknown whether pepcans occur in the periphery and interact with peripheral CB2 cannabinoid receptors. (siliconinvestor.com)
