ALLOSTERIC EFFECT ON MUSCARINIC M(2)-RECEPTORS OF DERIVATIVES OF THE ALKANE-BIS-AMMONIUM COMPOUND W84 - COMPARISON WITH BISPYRIDINIUM TYPE ALLOSTERIC MODULATORS

The symmetrically shaped W84 = halimido-propyl)-N,N'-hexane-1,6-diyl-b is-ammonium dibromide is a potent allosteric stabilizer of antagonist- binding to cardiac muscarinic M(2)-receptors. The ability of unilatera lly shortened W84 derivatives to allosterically retard the dissociatio n of [H-3]N-methylscopolamine ([H-3]NMS) from M(2)-receptors was deter mined in porcine cardiac membranes (3 mM MgHPO4, 50 mM TrisHCl, pH 7.3 , 37 degrees C). Shortening was accompanied by a reduction of the allo steric activity. For instance, W84 prolonged the half-life of [H-3]NMS dissociation (control t(1/2) = 2.0 min) by a factor of 2 at a concent ration of EC(50) = 1.3 mu M, whereas a derivative unilaterally lacking phthalimidopropyl- dimethylammonium was 40-fold less potent. It is co ncluded that the whole W84 molecule interacts with the allosteric site of the receptor. The structure-activity relationships found with this series of agents did not parallel findings made previously with simil arly modified derivatives of the bispyridinium compound DUO 3, ichloro benzoxyl)imino]methyl]pyridinium]dibromide, despite considerable simil arity with respect to molecular shape and charge distribution.