ASSESSMENT OF THE ALLOSTERIC INTERACTIONS OF THE BISQUATERNARY ANE-1,7-BIS(DIMETHYL-3'-PHTHALIMIDOPROPYL)AMMONIUM BROMIDE AT M(1) AND M(2) MUSCARINE RECEPTORS

The interaction of the allosteric muscarine receptor antagonist ane-1, 7-bis(dimethyl-3'-phthalimidopropyl)ammonium bromide (C-7/3-phth) with M(1) muscarine receptors in rat cerebral cortex and rabbit vas defere ns and M(2) muscarine receptors in guinea pig atria was investigated. In atria, C-7/3-phth completely inhibited the dissociation of N-[H-3]m ethylscopolamine ([H-3]NMS) in the presence of excess unlabeled NMS an d slowed the washout of NMS in functional experiments. C-7/3-phth also produced supra-additive inhibition of the negative inotropic effects of carbachol when combined with NMS. This latter phenomenon was less p ronounced when pirenzepine (PZP) was used in place of NMS. Cooperativi ty factors for the interaction of C-7/3-phth with other antagonists we re obtained by fitting the data to a theoretical model for interaction between an agonist, a competitive antagonist, and an allosteric antag onist. The values obtained indicate that C-7/3-phth exhibits a greater degree of negative heterotropic cooperativity with PZP than with NMS at the M(2) muscarine receptor. In the rat cerebral cortex, C7(/)3-pht h slowed the dissociation of [H-3]NMS and [H-3]quinuclidinyl benzilate from the M(1)receptor to the same extent but appeared not to affect t he dissociation of [H-3]PZP. In rabbit vas deferens, the inhibitory ef fect of the combination of C-(7)/3-phth and atropine on the responses to McN-A-343 at the M(1) receptor was more pronounced than that of the combination of C-7/3-phth and PZP. Comparison of the findings for bot h central and peripheral M(1) receptors with those obtained for the ca rdiac M(2) receptor suggests that the allosteric interaction of C-7/3- phth is less evident at the M(1) receptor, particularly in the case of PZP.-