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Synthesis and Pharmacological Profile of a Series of 1-substituted-2-Carbonyl Derivatives of Diphenidol: Novel M4 Muscarinic Receptor Antagonists

[ Vol. 4 , Issue. 2 ]


Lucilla Varoli, Piero Angeli, Michela Buccioni, Silvia Burnelli, Nicola Fazio, Gabriella Marucci, Maurizio Recanatini and Santi Spampinato   Pages 121 - 128 ( 8 )


Novel 2-carbonyl analogues of diphenidol (1) - bearing lipophylic 1-substituents (2) - were synthesized starting from previously investigated diphenidol derivatives acting as M2-selective muscarinic antagonists. These compounds were tested for receptor binding affinity versus human muscarinic M1-M5 receptors stably expressed in CHO-K1 cells. Their activity in functional assays carried out on CHO-K1 cells expressing human M4 receptors (CHO-hM4) and on classical models of M1-M3 receptors, in guinea pig and rabbit tissue preparations, was also evaluated. Compound 2d showed an affinity of pKi = 7.73 at the human M4-receptor subtype with selectivity ratios ranging from 31-fold (M4/M5) to 60-fold (M4/M2). Interestingly this compound, in CHO-hM4 cells, blocked the inhibition of forskolin-activated cAMP accumulation produced by carbachol (IC50= 61 nM) whereas it was a weak muscarinic antagonist in functional tests carried out in guinea-pig and rabbit tissue expressing M1 (pKb = 5.96), M2 (pKb = 6.43) and M3 (pKb = 6.09) receptors. In conclusion, the modifications performed in this work on reference compounds led us to obtain surprisingly a M4 selective antagonist. Considering the therapeutic indications for M4 selective antagonists, compound 2d may serve as a novel lead compound for further optimization.


Muscarinic antagonists, subtype selectivity, diphenidol derivatives, binding studies, functional studies, cAMP


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

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