SEARCH FOR THE PHARMACOPHORE OF BISPYRIDINIUM-TYPE ALLOSTERIC MODULATORS OF MUSCARINIC RECEPTORS

The bis(dichlorobenzyl) ether of the bispyridinium oxime TMB 4 stabilizes antagonist binding to M(2)-cholinoceptors which is indicative of an allosteric action. More than 10 derivatives of the lead compound were synthesized to investigate structure-activity relationships. The allosteric potency of the compounds was indicated by the concentrations which retarded the rate of dissociation of [H-3]N-methylscopolamine from porcine cardiac cholinoceptors by a factor of 2 (EC(50)). Compared with TMB 4, the bis(dichlorobenzyl) derivative 4a displayed a more than 200-fold higher potency (EC(50) = 4.7 mu M). One of the dichlorobenzyl groups could be replaced by a methyl group without loss of activity (EC(50) = 4.5 mu M). Further shortening of this end of the molecule was accompanied by a moderate decline in potency to a minimum of EC(50) = 26 mu M. The second quaternary nitrogen was not a prerequisite for an allosteric activity. It is concluded that one half of the lead compound is pivotal for an interaction with the allosteric site of the M(2)-cholinoceptor, whereas the opposite end of the molecule modulates the allosteric activity.