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Bioorg Med Chem Lett. 2008 May 1;18(9):2972-6. doi: 10.1016/j.bmcl.2008.03.061. Epub 2008 Mar 23.

Diphenidol-related diamines as novel muscarinic M4 receptor antagonists.

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  • 1Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.


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.

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