Diphenidol-related diamines as novel muscarinic M4 receptor antagonists

A series of hydrochloride derivatives 2a – 9a and quaternary ammonium derivatives 3b – 9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M 1 –M 5 receptors expressed in CHO cells. Compound 8b , a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M 4 activity as competitive antagonist. Moreover 8b , acting as an allosteric modulator, was able to retard the dissociation rate of [ 3 H]- N -methylscopolamine from CHO-M 4 cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.