SYNTHESIS AND MUSCARINIC RECEPTORS AFFINITY OF A SERIES OF ANTAGONIST BIVALENT LIGANDS

A series of bivalent ligands (2-8) derived from 2,2-diphenyl-[1,3]-dioxolan-4-ylmethyl-d amine methiodide 1 has been synthesized and tested to evaluate affinity and selectivity for M(1), M(2) and M(3) muscarinic receptor subtypes. In order to study the contribution of the spacer and of a second cationic head to the binding process, unsymmetrical ligands (9,10) have also been prepared. The results, expressed in terms of pA(2) values, show that, although the spacer negatively affects the interaction of the bivalent ligands with the three receptor subtypes, affinity and selectivity are modulated by its length; this indicates that the pharmacophore binding sites are organized differently with respect to their mutual proximity and orientation, in each receptor subtype.