title: M2-muscarinic receptors: how does ligand binding affinity relate to intrinsic activity?
abstract: In this study we looked for evidence regarding a correlation between M2-muscarinic receptor binding affinity and ligand intrinsic activity. Guanine nucleotide-binding protein-coupled receptors have been shown to exist in both a high affinity and a low affinity, agonist state. The agonist [3H]Oxotremorine-M, was used to determine the affinity of compounds for the high affinity state and the antagonist, [3H]N-methylscopolamine, plus GppNHp, was used to determine the affinity for the low agonist state. The magnitude of the difference in the affinity a compound has for the high versus the low agonist state of the receptor has been related to the intrinsic activity of the compound. NMS/Oxo-M ratios were established for muscarinic agonists, partial agonists and antagonists. NMS/Oxo-M ratios varied from 1695 for the agonist carbachol to 1.9 for the antagonist AFDX-166 with intermediate values for the partial agonists oxotremorine-M, pilocarpine and RS86 (233, 36 and 17 respectively). Intrinsic activity was assessed by receptor-mediated Gi-protein GTPase activity. Indeed, a close correlation (r=0.92) was found between the NMS/Oxo-M ratios of the ligands on the one hand, and their ability to activate the M2-receptor coupled Gi-protein on the other.
authors.affiliation: Laboratoire de Neuroimmunopharmacologie, INSERM U-425, Université Louis Pasteur-Strasbourg I, Illkirch, France.
authors.forename: J G
authors.initials: JG
authors.lastname: Van Gelderen
authors.forename: L
authors.initials: L
authors.lastname: Daeffler
authors.forename: D
authors.initials: D
authors.lastname: Scherrer
authors.forename: M
authors.initials: M
authors.lastname: Mousli
authors.forename: Y
authors.initials: Y
authors.lastname: Landry
authors.forename: J P
authors.initials: JP
authors.lastname: Gies
mesh_terms: D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006325:Heart Atria / Q000378:metabolism; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000031:analogs & derivatives / Q000378:metabolism; D010276:Parasympatholytics / Q000378:metabolism; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000378:metabolism*; D012602:Scopolamine Derivatives / Q000378:metabolism; D013552:Swine
chemical_list: D010276:Parasympatholytics; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D006165:Guanylyl Imidodiphosphate; D010095:Oxotremorine; C042743:oxotremorine M; D002217:Carbachol; D020558:GTP Phosphohydrolases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019832:N-Methylscopolamine