title: G-protein coupled receptors as allosteric machines.
abstract: Allosterism, whereby small molecule ligands produce global changes in the conformations of receptors, is a powerful mechanism for drug effect. This is illustrated by the recent data describing CCR5 antagonists as blockers of HIV infection. Allosteric effects are described in terms of a change in the tertiary conformation of the receptor. This paper outlines some unique features of allosteric antagonists as new drug entities. These include the fact that allosteric ligands have texture in antagonism (not all allosterically blocked receptors are alike), allosteric blockade is probe dependent (not all agonists and radioligands are blocked equally), and the fact that allosteric binding involves a separate site on the receptor may have relevance to duration of effect and selectivity. Dissociation between receptor function and binding also can be encountered with allosteric ligands.
authors.affiliation: Molecular Discovery, GlaxoSmithKline Research and Development, 5 Moore Drive, RTP 27709, USA. terry.p.kenakin@gsk.com
authors.forename: Terry
authors.initials: T
authors.lastname: Kenakin
mesh_terms: D000443:Alcuronium / Q000494:pharmacology; D000494:Allosteric Regulation; D000495:Allosteric Site; D019380:Anti-HIV Agents / Q000494:pharmacology; D065100:CCR5 Receptor Antagonists; D005703:Gallamine Triethiodide / Q000494:pharmacology; D015658:HIV Infections / Q000188:drug therapy / Q000517:prevention & control; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D008024:Ligands; D043585:Receptor, Muscarinic M2; D019718:Receptors, CXCR4; D043562:Receptors, G-Protein-Coupled; D005703:Gallamine Triethiodide; D000443:Alcuronium