PSEUDO-NONCOMPETITIVE ANTAGONISM OF M-1, M-3, AND M-5, MUSCARINIC RECEPTOR-MEDIATED CA2- MOBILIZATION BY MUSCARINIC ANTAGONISTS

Muscarinic receptors M-1, M-3 and M-5 were expressed in Sf9 cells, Thr ee different patterns of inhibition of Ca2+ elevations could be resolv ed for the subtype non-selective muscarinic receptor antagonists: (i) a right shift of the agonist dose-response curve, (ii) a right shift o f the agonist dose-response curve and a depression of the maximum sign al, and (iii) an intermediate pattern where the antagonist apparently behaved more competitively at higher concentrations, A simulation perf ormed assuming that these differences are due to differences in the di ssociation rates of the antagonists reproduced all three different mod es of inhibition; the novel intermediate pattern (iii) is suggested to be caused by an intermediate antagonist dissociation rate, A direct c orrelation between the type of inhibition and the measured dissociatio n rate of the antagonists was also observed, Functional selectivity be tween receptor subtypes based on the dissociation constants is suggest ed based on the results, (C) 1998 Academic Press.