CONTRIBUTION OF LATERAL SUBSTITUENTS IN HEPTANE-BISAMMONIUM DERIVATIVES TO THE ALLOSTERIC STABILIZATION OF ANTAGONIST BINDING TO M-2-RECEPTORS

Phthalimide-containing heptane-bisammonium-type compounds retard the d issociation of the antagonist [H-3]-N-methylscopolamine ([H-3]NMS) fro m muscarinic M-2-receptor allosterically with high potency. To study t he contribution of the lateral substituents to this effect, a series o f derivatives was synthesized in which the phthalimide moiety was trun cated. The potency of the compounds to delay [H-3]NMS dissociation was measured in porcine heart homogenates (50 mM Tris-HCl 3 mM MgHPO4, pH 7.3, 37 degrees C). Potency declined with diminuition of the lateral substituents, e.g. loss of the aromatic ring of the phthalimide result ed in a 400fold reduction in potency. In the hexahydrophthalimide deri vatives, the cis-stereoisomer was about fivefold more potent than the trans-isomer. In conclusion, almost flat hydrophobic lateral moieties appear to be pivotal for high allosteric potency, suggesting a hydroph obic interaction of these parts of the molecule with the [H-3]NMS occu pied receptor protein.