Dissociation constants and relative efficacies of acetylcholine, (+)‐ and (‐)‐methacholine at muscarinic receptors in the guinea‐pig ileum

Abstract

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 μM, 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. 1986 British Pharmacological Society