M2-muscarinic receptors: how does ligand binding affinity relate to intrinsic activity?

J Recept Signal Transduct Res. Jan-Mar 1996;16(1-2):135-48. doi: 10.3109/10799899609039945.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Oxotremorine / metabolism
  • Parasympatholytics / metabolism
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic / metabolism*
  • Scopolamine Derivatives / metabolism
  • Swine

Substances

  • Parasympatholytics
  • Receptor, Muscarinic M2
  • Receptors, Muscarinic
  • Scopolamine Derivatives
  • Guanylyl Imidodiphosphate
  • Oxotremorine
  • oxotremorine M
  • Carbachol
  • GTP Phosphohydrolases
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • N-Methylscopolamine