Dissociation constants and relative efficacies of acetylcholine, (+)- and (-)-methacholine at muscarinic receptors in the guinea-pig ileum.
Dissociation constants (KA) and relative efficacies of acetylcholine, (+)-methacholine and (-)-methacholine at muscarinic receptors in the guinea-pig isolated ileum were determined in the absence and presence of the cholinesterase inhibitor diisopropylfluorophosphate. The method used involved analysis of dose-response data before and after fractional inactivation of receptors with propylbenzilylcholine mustard. The KA values, estimated after cholinesterase inhibition, of acetylcholine, (+)- and (-)-methacholine were 1.7, 2.0 and 620 microM, respectively. The large (730 fold) difference in spasmogenic activity between (+)- and (-)-methacholine is due primarily to a difference in affinity for ileal muscarinic receptors although differences in efficacy (2 to 4 fold) also contribute. It is suggested that the methyl group at the chiral centre of (+)-methacholine has no apparent effect on the binding to muscarinic receptors, whereas the corresponding methyl group of (-)-methacholine interferes with binding, presumably by stabilizing a conformation of the drug which does not fit the receptor very well.
D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007531:Isoflurophate / Q000494:pharmacology; D008297:Male; D008688:Methacholine Compounds / Q000494:pharmacology*; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011976:Receptors, Muscarinic / Q000187:drug effects*
D008688:Methacholine Compounds; D011976:Receptors, Muscarinic; D007531:Isoflurophate; D000109:Acetylcholine