Allosteric effect on muscarinic M2-receptors of derivatives of the alkane-bis-ammonium compound W84. Comparison with bispyridinium-type allosteric modulators

Article abstract of DOI:10.1016/0223-5234(94)90194-5

The symmetrically shaped W84 = N,N,N',N'-tetramethyl-N,N'-bis-(3-phthalimido-propyl)-N,N'-hexane-1,6-diyl-bisammonium dibromide is a potent allosteric stabilizer of antagonist-binding to cardiac muscarinic M₂-receptors.The ability of unilaterally shortened W84 derivatives to allosterically retard the dissociation of <3H>N-methylscopolamine (<3H>NMS) from M₂-receptors was determined in porcine cardiac membranes (3 mM MgHPO4, 50 mM TrisHCl, pH 7.3, 37 deg C).Shortening was accompanied by a reduction of the allosteric activity.For instance, W84 prolonged the half-lif e of <3H>NMS dissociation (control t_1/2 = 2.0 min) by a factor of 2 at a concentration of EC50 = 1.3 μM, whereas a derivative unilaterally lacking phthalimidopropyldimethylammonium was 40-fold less potent.It is concluded that the whole W84 molecule interact with the allosteric site of the receptor.The structure-activity relationships found with this series of agents did not parallel findings made previously with similarly modified derivatives of the bispyridinium compound DUO 3, (E,E)-1,1'-(1,3-propanediyl)-bis<4-<<(2,6-dichlorobenzoxyl)imino>methyl>pyridinium>dibromide, despite considerable similarity with respect to molecular shape and charge distribution. muscarinic receptor/ porcine myocardium/ allosteric modulation/ W84/ structure-activity relationship