Bisquaternary ligands of the common allosteric site of M-2 acetylcholine receptors: Search for the minimum essential distances between the pharmacophoric elements

Structurally diverse molecules, such as alcuronium, gallamine, and tubocura rine as well as W84 and WDUO, are known to interact allosterically with lig and binding to muscarinic Ma acetylcholine receptors. Preliminary molecular modeling studies revealed two positive charges in the middle and two later al aromatic areas to be essential elements of a high allosteric potency. To find out the optimum distances between these pharmacophoric elements, a sy stematic variation of the spacer in the series of W84, WDUO, and IWDUO comp ounds was performed. The allosteric reduction of the rate of dissociation o f the antagonist [H-3]-N-methylscopolamine from porcine heart M-2 receptors served as a test system. The minimal essential distance between the positi ve charges was found to be 10 Angstrom. The length of the peripheral spacer s connecting the positive charge and the lateral aromatic moiety appears to depend on the chemical functionality; the peripheral spacers have to be lo ng and flexible enough to position the aromatic skeletons in the spatial ne ighborhood of the alkane middle chain: in the case of an oxime ether contai ning peripheral spacer, six atoms are required, and in the case of an alkan e chain, four carbon atoms are necessary to adopt the pharmacophoric S-shap e conformation.