Elevation of Ligand Binding to Muscarinic M₂ Acetylcholine Receptors by Bis(ammonio)alkane-Type Allosteric Modulators

Bis(ammonio)alkane-type compounds are archetypal muscarinic allosteric modulators. Phthalimido-substituted hexane-bis-ammonium agents were methylated in the phthalimide moieties and the lateral propyl side chains. All compounds retarded allosterically the dissociation of the orthosteric ligand [³H]N-methylscopolamine ([³H]NMS) from porcine heart M₂ receptors. [³H]NMS equilibrium binding was reduced, left unaltered, or elevated, depending on the degree and position of methylation. This is the first time that an allosteric elevation of ligand binding is demonstrated for bis(ammonio)alkane-type compounds.