CONFORMATIONAL-ANALYSIS, MOLECULAR SHAPE COMPARISON, AND PHARMACOPHORE IDENTIFICATION OF DIFFERENT ALLOSTERIC MODULATORS OF MUSCARINIC RECEPTORS

Structurally dissimilar compounds such as alcuronium and the newly syn thesized substances derived from the bisbenzyl ether TMB4 and from hex amethonium stabilize antagonist binding to M(2)-cholinoceptors which i s indicative of an allosteric action. in order to propose a hypothesis for the common pharmacophore and the corresponding active conformatio ns, seven flexible compounds in a data set were individually aligned o nto the most active and, additionally, rigid alcuronium molecule using a torsional angle flexible fit. An S-shape conformation was found to be a plausible general active conformation. In a subsequent molecular shape analysis the overlap and the nonoverlap steric volumes, RMS alig nment as well as electrostatic field potentials were employed as possi ble structure-activity correlation descriptors. The corresponding 3D-Q SAR formulation exhibits a correlation between allosteric modulation p otency and the nonoverlap steric volume as well as the proton and oxyg en anion probe electrostatic field potentials. Because of large struct ural diversity among the small number of compounds studied, the appare nt 3D-QSAR is best thought of as a convenient representation of the co mmon spatial pharmacophore hypothesis.