VARIATION OF THE OXIME FUNCTION OF BISPYRIDINIUM-TYPE ALLOSTERIC MODULATORS OF M(2)-CHOLINOCEPTORS

The bisbenzylether of the bispyridinium oxime, DUO 3-O imino)-methyl]- 1,1'-propane-1,3-diyl-bispyridinium dibromide), has been found to stab ilize the antagonist binding to the M(2)-cholinoceptors which is indic ative of an allosteric action. The oxygen of the oxime group was repla ced with a nitrogen and a CH2-group leading to DUO 3-N and 3-C, respec tively. The allosteric potency of the compounds was characterized by t he concentrations which retarded the rate of dissociation of [H-3]N-me thylscopolamine from porcine cardiac cholinoceptors by a factor of 2 ( EC(50)). The hydrazone derivative DUO 3-N was found to be the most act ive compound (ED(50) = 2.7 mu M) exceeding in activity DUO 3-0 by a fa ctor of 1.6 and DUO 3-C by a factor of 5. No correlation was found bet ween the lipophilicity, determined as octanol/water partition coeffici ent, and the allosteric potency. The distribution of charges in the mo lecules was calculated by means of PEOE and displayed as Kohonen maps: The calculations exhibit a shift of the positive charge in the pyridi nium ring from the nitrogen to the carbon atom in para-position when g oing from DUO 3-O to 3-O and 3-N. This shift parallels the rank order of the allosteric potency. From these results the conclusion has been drawn that the between distance the terminal ring-system and the posit ive charge is pivotal for the interaction of the allosteric modulators with the receptor protein.