A STABLE AND HIGHLY POTENT HEXAMETHONIUM DERIVATIVE WHICH MODULATES MUSCARINIC RECEPTORS ALLOSTERICALLY IN GUINEA-PIG HEARTS

W84 (N,N, N',N '-tetramethyl-N,N '-bis-(3-phthalimidopropyl)-N,N '-hex ane-1,6-diyl-bis-ammonium dibromide) is a potent stabilizer of antagon ist binding to muscarinic receptors; however, W84 hydrolyses in aqueou s buffered medium. The synthesis of the stable derivative CHIN3/6 is p resented containing a 2-phenyl-quinazolinone instead of the labile pht halimide substituent. This compound retarded [H-3]N-methylscopolamine- dissociation in guinea-pig cardiac membranes with slightly higher pote ncy than W84, the EC50 values amounting to 7.5 x 10(-7) and 13 x 10(-7 ) M, respectively. Molecular modelling revealed differences in the ele ctron density of the substituents and in their molecular shape. It is suggested that the derivatives use partially different sites of attach ment when occupying the allosteric binding site of the receptor protei n.