• ligands
  • It has been reported that the repertoire of GPCRs for endogenous ligands consists of approximately 400 receptors in humans and mice [ PMID: 12679517 ]. (ebi.ac.uk)
  • Although their activating ligands vary widely in structure and character, the amino acid sequences of the receptors are very similar and are believed to adopt a common structural framework comprising 7 transmembrane (TM) helices [ PMID: 2111655 , PMID: 2830256 , PMID: 8386361 ]. (ebi.ac.uk)
  • Unlike other known opioid-receptor ligands, salvinorin A is not an alkaloid as it does not contain a basic nitrogen atom. (wikipedia.org)
  • Through activation of the KOR, dynorphins, opioid peptides that are the endogenous ligands of the KOR and that can, in many regards, be figuratively thought of as functional inverses of the morphine-like, euphoric and stress-inhibiting endorphins, induce dysphoria and stress-like responses in both animals and humans, as well as psychotomimetic effects in humans, and are thought to be essential for the mediation of the dysphoric aspects of stress. (wikipedia.org)
  • Trevena Inc is a clinical stage biopharmaceutical company, headquartered in Chesterbrook, Pennsylvania, USA, and is involved in the discovery and development of G-protein coupled receptors (GPCR) biased ligands. (wikipedia.org)
  • Trevena has received funding from the Michael J. Fox Foundation to explore the potential for delta opioid receptor biased ligands to treat Parkinson's disease. (wikipedia.org)
  • proteins
  • The rhodopsin-like GPCRs (GPCRA) represent a widespread protein family that includes hormone, neurotransmitter and light receptors, all of which transduce extracellular signals through interaction with guanine nucleotide-binding (G) proteins. (ebi.ac.uk)
  • The first method (proteomic screen) involved pulling out the receptor and proteins bound to the receptor after drug activation using a technique called co-immunoprecipitation. (newswise.com)
  • Once isolated, the receptor and the proteins bound to it may be identified by mass spectrometry. (newswise.com)
  • Expression of opioid receptor proteins is controlled by extensive transcriptional and post-transcriptional processing. (nih.gov)
  • This includes downregulation of MOR gene expression, so the number of receptors presented on the cell surface is actually reduced, as opposed to the more short-term desensitisation induced by β-arrestins or RGS proteins. (wikipedia.org)
  • affinity
  • This suggests that substitution at both the 3 and 4 positions of the piperidine ring introduces steric hindrance which prevents μ-opioid affinity from increasing much further. (wikipedia.org)
  • Another side effect which is characteristic of fentanyl and its derivatives is their tendency to rapidly induce tolerance, due to their high binding affinity triggering rapid internalization of chronically activated opiate receptors. (wikipedia.org)
  • It has a high affinity for the receptor, indicated by the low dissociation constant of 1.0 nanomolar (nM). (wikipedia.org)
  • agonists
  • At concentrations that reduced evoked EPSP/EPSCs by 40-60%, neither DAMGO, DPDPE, nor DELT decreased the amplitude of the postsynaptic current produced by brief pressure ejection of (S)-alpha-amino-3-hydroxy-5- methyl-4-isoxazole-propionic acid, suggesting a presynaptic site of action of these opioid receptor agonists. (jneurosci.org)
  • Activation of these receptors inhibits peristaltic action which causes constipation, a major side effect of μ agonists. (wikipedia.org)
  • It has been used as a lead compound to derive further analogues, although all compounds in this family are comparatively weak mu agonists. (wikipedia.org)
  • morphine-induced
  • mE7M-B6 mutant mice lost morphine-induced receptor desensitization in the brain stem and hypothalamus, consistent with exon 7 involvement in morphine tolerance. (jci.org)
  • In cell-based studies, exon 7-associated variants shifted the bias of several mu opioids toward β-arrestin 2 over G protein activation compared with the exon 4-associated variant, suggesting an interaction of exon 7-associated C-terminal tails with β-arrestin 2 in morphine-induced desensitization and tolerance. (jci.org)
  • The canonical MOR1 isoform is responsible for morphine-induced analgesia, whereas the alternatively spliced MOR1D isoform (through heterodimerization with the gastrin-releasing peptide receptor) is required for morphine-induced itching. (wikipedia.org)
  • Imax = 29%) with lower relative intrinsic activity and marked antagonistic potential (including the ability to antagonize morphine-induced effects and induce opioid withdrawal in opioid-dependent individuals). (wikipedia.org)
  • activation
  • Newswise - March 7, 2014, Phoenix, AZ -- Researchers found initial confirmation that a novel scaffold protein previously unassociated with the mu opioid receptor (MOR) regulates MOR-induced signaling activation. (newswise.com)
  • This study examined the electrophysiological consequences of selective activation of delta 1-, delta 2-, or mu-opioid receptors using whole- cell recordings made from visually identified lamina II neurons in thin transverse slices of young adult rat lumbar spinal cord. (jneurosci.org)
  • Activation of the MOR leads to different effects on dendritic spines depending upon the agonist, and may be an example of functional selectivity at the μ-receptor. (wikipedia.org)
  • Activation of the μ-opioid receptor by an agonist such as morphine causes analgesia, sedation, slightly reduced blood pressure, itching, nausea, euphoria, decreased respiration, miosis (constricted pupils), and decreased bowel motility often leading to constipation. (wikipedia.org)
  • Another long-term adaptation to opioid use can be upregulation of glutamate and other pathways in the brain which can exert an opioid-opposing effect, so reduce the effects of opioid drugs by altering downstream pathways, regardless of MOR activation. (wikipedia.org)
  • and activation of the μ-opioid receptor causes analgesic and euphoriant effects. (wikipedia.org)
  • This might be expected to be a particular problem with lofentanil as it is not only one of the most potent drugs in the series, but also is longer acting than most other fentanyl analogues, meaning that development of tolerance triggered by receptor over-activation could be rapid. (wikipedia.org)
  • potent
  • It is most similar to the highly potent opioid carfentanil (4-carbomethoxyfentanyl), only slightly more potent. (wikipedia.org)
  • Research has shown that salvinorin A is a potent κ-opioid receptor (KOR) agonist (Ki = 2.4 nM, EC50 = 1.8 nM). (wikipedia.org)
  • For instance, it is 40-fold less potent in promoting internalization (that is, receptor downregulation) of the human KOR relative to the prototypical KOR agonist U-50488.The drug has been found not to produce diuresis in mice, possibly due to its short duration. (wikipedia.org)
  • Salvinorin A is capable of inhibiting excess intestinal motility (e.g. diarrhea), through its potent k-opioid-activating effects. (wikipedia.org)
  • pathways
  • While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the m-opioid receptor (mOR)and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. (epfl.ch)
  • analgesia
  • The long duration and high lipophilicity of lofentanil has been suggested as an advantage for certain types of analgesia, but the main application for lofentanil at the present time is research into opioid receptors. (wikipedia.org)
  • acute
  • Trevena's leading drug candidate is Oliceridine (TRV130), a G protein-biased ligand binding to the mu opioid receptor for the intravenous treatment of acute moderate-to-severe post-operative pain. (wikipedia.org)
  • Trevena's developed TRV027 for acute heart failure, targets the angiotensin receptor utilizing beta-arrestin bias, an approach that has shown numerous beneficial cardiovascular and renal actions in preclinical species. (wikipedia.org)
  • dependence
  • It was approved in 1993 by the U.S. Food and Drug Administration for use in the treatment of opioid dependence. (wikipedia.org)
  • LAAM is indicated as a second-line treatment for the treatment and management of opioid dependence if patients fail to respond to drugs like methadone or buprenorphine. (wikipedia.org)
  • This unique benefit makes long-term low-dose treatment of chronic pain and/or opioid dependence with dezocine more feasible than with most other opioids. (wikipedia.org)
  • Targeting
  • Other delta opioid-targeting drugs are known to cause seizures, but Trevaga hopes to avoid this with TRV250 by bypassing the β-arrestin pathway. (wikipedia.org)
  • downstream
  • The precise mechanism of action in explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergic neuromodulation, among other properties. (wikipedia.org)
  • mechanism
  • The MOR is the target of opioid drugs like morphine and is an important mechanism for pain regulation in the body. (newswise.com)
  • To elucidate the effect of an opioid on airway smooth muscle relaxant responses and its mechanism of action, we studied canine bronchial segments under isometric conditions in vitro. (aspetjournals.org)
  • effects
  • As such, its effects do not rely on the cognate membrane receptors. (wikipedia.org)
  • It is a useful drug for the treatment of pain, but side effects such as dizziness limit its clinical application, and it can produce opioid withdrawal syndrome in patients already dependent on other opioids. (wikipedia.org)
  • This suggests that the D2 receptor may also play an important role in its effects. (wikipedia.org)