M2-muscarinic receptors: how does ligand binding affinity relate to intrinsic activity?
Fiche publication
Journal
Journal of receptor and signal transduction research
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GIES Jean-Pierre, Dr DAEFFLER Laurent, Dr MOUSLI Marc
Tous les auteurs :
Van Gelderen JG, Daeffler L, Scherrer D, Mousli M, Landry Y, Gies JP
Lien Pubmed
Résumé
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.
Mots clés
Animals, Binding Sites, Binding, Competitive, Carbachol, pharmacology, GTP Phosphohydrolases, metabolism, GTP-Binding Protein alpha Subunits, Gi-Go, metabolism, Guanylyl Imidodiphosphate, pharmacology, Heart Atria, metabolism, N-Methylscopolamine, Oxotremorine, analogs & derivatives, Parasympatholytics, metabolism, Receptor, Muscarinic M2, Receptors, Muscarinic, metabolism, Scopolamine Derivatives, metabolism, Swine
Référence
J. Recept. Signal Transduct. Res.. ;16(1-2):135-48