International Union of Pharmacology. XXIX. Update on endothelin receptor nomenclature.
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In mammals, the endothelin (ET) family comprises three endogenous isoforms, ET-1, ET-2, and ET-3. ET-1 is the principal isoform in the human cardiovascular system and remains the most potent and long-lasting constrictor of human vessels discovered. In humans, endothelins mediate their actions via only two receptor types that have been cloned and classified as the ET(A) and ET(B) receptors in the first NC-IUPHAR (International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification) report on nomenclature in 1994. This report was compiled before the discovery of the majority of endothelin receptor antagonists (particularly nonpeptides) currently used in the characterization of receptors and now updated in the present review. Endothelin receptors continue to be classified according to their rank order of potency for the three endogenous isoforms of endothelin. A selective ET(A) receptor agonist has not been discovered, but highly selective antagonists include peptides (BQ123, cyclo-[D-Asp-L-Pro-D-Val-L-Leu-D-Trp-]; FR139317, N- [(hexahydro-1-azepinyl)carbonyl]L-Leu(1-Me)D-Trp-3 (2-pyridyl)-D-Ala) and the generally more potent nonpeptides, such as PD156707, SB234551, L754142, A127722, and TBC11251. Sarafotoxin S6c, BQ3020 ([Ala(11,15)]Ac-ET-1((6-21))), and IRL1620 [Suc-(Glu(9), Ala(11,15))-ET-1((8-21))] are widely used synthetic ET(B) receptor agonists. A limited number of peptide (BQ788) and nonpeptide (A192621) ET(B) antagonists have also been developed. They are generally less potent than ET(A) antagonists and display lower selectivity (usually only 1 to 2 orders of magnitude) for the ET(B) receptor. Radioligands highly selective for either ET(A) ((125)I-PD151242, (125)I-PD164333, and (3)H-BQ123) or ET(B) receptors ((125)I-BQ3020 and (125)I-IRL1620) have further consolidated classification into only these two types, with no strong molecular or pharmacological evidence to support the existence of further receptors in mammals. (+info)
International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature.
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An update of the International Union of Pharmacology nomenclature for chemokines is outlined, defining one new receptor type, CXCR6, and disqualifying the putative receptor, CCR11. (+info)
International Union of Pharmacology. XXXI. Recommendations for the nomenclature of multimeric G protein-coupled receptors.
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A receptor is defined by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR) as a protein, or a complex of proteins, which recognizes physiologically relevant ligands that can regulate the protein to mediate cellular events (Ruffolo et al., 2000). This definition does not include associated proteins, which are not required for agonist recognition and/or receptor assembly. Thus, G proteins are not included in the nomenclature of G protein-coupled receptors (GPCRs). Similarly, proteins which modify receptor disposition, such as proteins with a PDZ domain (Sheng and Sala, 2001), and which associate with the cytosolic portion of the receptor are not included. The question arises, however, as to the way to name multimeric receptors where subunits influence receptor assembly and agonist recognition. The essential issue is whether to name the individual proteins or the association of proteins? NC-IUPHAR recommends that, where possible, the functional receptor complex be given a different name from that of the subunits. (+info)
International Union of Pharmacology. XXXII. The mammalian calcitonin gene-related peptides, adrenomedullin, amylin, and calcitonin receptors.
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The calcitonin family of peptides comprises calcitonin, amylin, two calcitonin gene-related peptides (CGRPs), and adrenomedullin. The first calcitonin receptor was cloned in 1991. Its pharmacology is complicated by the existence of several splice variants. The receptors for the other members the family are made up of subunits. The calcitonin-like receptor (CL receptor) requires a single transmembrane domain protein, termed receptor activity modifying protein, RAMP1, to function as a CGRP receptor. RAMP2 and -3 enable the same CL receptor to behave as an adrenomedullin receptor. Although the calcitonin receptor does not require RAMP to bind and respond to calcitonin, it can associate with the RAMPs, resulting in a series of receptors that typically have high affinity for amylin and varied affinity for CGRP. This review aims to reconcile what is observed when the receptors are reconstituted in vitro with the properties they show in native cells and tissues. Experimental conditions must be rigorously controlled because different degrees of protein expression may markedly modify pharmacology in such a complex situation. Recommendations, which follow International Union of Pharmacology guidelines, are made for the nomenclature of these multimeric receptors. (+info)
International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function.
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The gamma-aminobutyric acid(B) (GABA(B)) receptor was first demonstrated on presynaptic terminals where it serves as an autoreceptor and also as a heteroreceptor to influence transmitter release by suppressing neuronal Ca(2+) conductance. Subsequent studies showed the presence of the receptor on postsynaptic neurones where activation produces an increase in membrane K(+) conductance and associated neuronal hyperpolarization. (-)-Baclofen is a highly selective agonist for GABA(B) receptors, whereas the established GABA(A) receptor antagonists, bicuculline and picrotoxin, do not block GABA(B) receptors. The receptor is G(i)/G(o) protein-coupled with mixed effects on adenylate cyclase activity. The receptor comprises a heterodimer with similar subunits currently designated 1 and 2. These subunits are coupled via coiled-coil domains at their C termini. The evidence for splice variants is critically reviewed. Thus far, no unique pharmacological or functional properties have been assigned to either subunit or the variants. The emergence of high-affinity antagonists for GABA(B) receptors has enabled a synaptic role to be established. However, the antagonists have generally failed to establish the existence of pharmacologically distinct receptor types within the GABA(B) receptor class. The advent of GABA(B1) knockout mice has also failed to provide support for multiple receptor types. (+info)
International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature.
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The lysophospholipids, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), are now recognized as important extracellular signaling molecules. These lipid mediators are pleiotropic; among the most common cellular responses are mitogenesis, cell survival (anti-apoptosis), inhibition of adenylyl cyclase and calcium mobilization. Physiologic events associated with these mediators include platelet aggregation, vasopressor activity, wound healing, immune modulation, and angiogenesis. Many of the actions of LPA and S1P are mediated through a set of eight G protein-coupled receptors. Five of these are S1P-prefering while the remaining three are LPA receptors. These receptors are expressed widely and in aggregate signal through a variety of heterotrimeric G proteins. The lysophospholipid receptor family is referred to commonly as the "Edg" group (e.g., Edg-1, Edg-2, etc.). Herein, the molecular pharmacology of the lysophospholipid receptors is reviewed briefly, and a rational nomenclature for LPA and S1P receptors that is consistent with the International Union of Pharmacology guidelines is proposed. (+info)
Eliminating iodine deficiency disorders--the role of the International Council in the global partnership.
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Iodine deficiency is the most common preventable cause of brain damage. WHO estimates that some 2.2 billion people are at risk from iodine deficiency in 130 countries. A programme of universal salt iodization was established in 1994 with the aim of eliminating the problem by 2000. This paper reports progress in this field, with particular reference to the primarily scientific role of the International Council for Control of Iodine Deficiency Disorders, a nongovernmental organization founded in 1986. It is now a multidisciplinary network of 600 professionals in 100 countries. (+info)
International Conference on Harmonisation: guidance on Q1D bracketing and matrixing designs for stability testing of new drug substances and products; availability. Notice.
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The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products." The guidance was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance is an annex to an ICH guidance entitled "Q1A(R) Stability Testing of New Drug Substances and Products" (66 FR 56332, November 7, 2001). It is intended to provide guidance on the application of reduced designs (i.e., bracketing and matrixing) for stability studies conducted in accordance with the principles outlined in ICH Q1A(R). (+info)