Characterization of the antimuscarinic effect of heptane-1,7-bis-(dimethyl-3′-phthalimidopropyl ammonium bromide)

Abstract

The effect of heptane-1,7-bis-(dimethyl-3′-phthalimidopropyl bromide) (C 7/3′-phtalimidopropyl), an alkane bisquaternary compound with muscarinic receptor blocking activity was studied in guinea-pig atria and ileal longitudinal muscle. C 7/3′-phthalimidopropyl was a more potent inhibitor of atrial muscarinic receptors, the cardioselectivity being ca. 32-fold. Previous studies in guinea-pig atria have shown that its antimuscarinic effect was of an allosteric nature. In ileal longitudinal muscle C 7/3′-phthalimidopropyl (3 to 100 μM) appeared to behave in a competitive manner towards carbachol but the combination of atropine or homatropine with C 7/3′-phthalimidopropyl produced a supra-additive inhibitory effect on the responses to carbachol. In both atria and ileal longitudinal muscle homogenates, C 7/3′-phthalimidopropyl also slowed the dissociation rate of [ 3H]QNB suggesting an allosteric mechanism. In binding studies using either [ 3H]QNB or [ 3H]oxo-M, C 7/3′-phthalimidopropyl recognized two binding sites in atria and ileum. In both tissues, C 7/3′-phthalimidopropyl bound with high affinity (ca. 30–70 nM) to 60–85% of the sites and with low affinity (ca. 1–9 μM) to the remaining sites. Correlation of these affinity constants with the dissociation constants obtained in functional studies in the two tissues isdiscussed.