Antimuscarinic action of an alkane-bis-ammonium compound alone and in combination with (+)-benzetimide.

Heptane-1,7-bis-(dimethyl-3'-phthalimidopropylammonium bromide) ('C7/3-phthalimido-propyl') in concentrations of 10(-7) to 0.5 X 10(-3) inhibited negative inotropic responses to carbachol or acetylcholine to a similar extent in the electrically stimulated isolated guinea-pig left atrium. However, the degree of antagonism of responses to carbachol was less than expected for a competitive antagonist when the higher concentrations of 'C7/3-phthalimido-propyl' were employed. When 'C7/3-phthalimido-propyl' was combined with competitive antagonists such as (+)-benzetimide, atropine or homatropine the degree of antagonism was greater than expected for combination of 2 competitive antagonists. Qualitatively similar results were obtained in the presence of practolol (1.5 X 10(-5) M). The results obtained with 'C7/3-phthalimido-propyl' are shown to agree with theoretical predictions for a metaffinoid antagonist which influences the affinities of both agonists and competitive antagonists by combining with a regulatory site distinct from, but interdependent with the binding sites for agonists and competitive antagonists. Further, it is shown that the alkane-bis-ammonium compound produces a much greater reduction in the affinity of carbachol than that of the competitive antagonists and as a consequence causes 'supra-additive' effects when combined with a competitive antagonist. The reduction in the affinity of (+)-benzetimide produced by 'C7/3-phthalimido-propyl' did not differ significantly from the reduction in the affinities of atropine or homatropine.