title: Synthesis and pharmacological profile of a series of 1-substituted-2-carbonyl derivatives of Diphenidol: novel M4 muscarinic receptor antagonists.
abstract: Novel 2-carbonyl analogues of diphenidol (1) - bearing lipophylic 1-substituents (2) - were synthesized starting from previously investigated diphenidol derivatives acting as M(2)-selective muscarinic antagonists. These compounds were tested for receptor binding affinity versus human muscarinic M(1)-M(5) receptors stably expressed in CHO-K1 cells. Their activity in functional assays carried out on CHO-K1 cells expressing human M(4) receptors (CHO-hM(4)) and on classical models of M(1)-M(3) receptors, in guinea pig and rabbit tissue preparations, was also evaluated. Compound 2d showed an affinity of pK(i) = 7.73 at the human M(4)-receptor subtype with selectivity ratios ranging from 31-fold (M(4)/M(5)) to 60-fold (M(4)/M(2)). Interestingly this compound, in CHO-hM(4) cells, blocked the inhibition of forskolin-activated cAMP accumulation produced by carbachol (IC(50)= 61 nM) whereas it was a weak muscarinic antagonist in functional tests carried out in guinea-pig and rabbit tissue expressing M(1) (pK(b) = 5.96), M(2) (pK(b) = 6.43) and M(3) (pK(b) = 6.09) receptors. In conclusion, the modifications performed in this work on reference compounds led us to obtain surprisingly a M(4) selective antagonist. Considering the therapeutic indications for M(4) selective antagonists, compound 2d may serve as a novel lead compound for further optimization.
authors.affiliation: Department of Pharmaceutical Sciences, University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy. lucilla.varoli@unibo.it
authors.forename: Lucilla
authors.initials: L
authors.lastname: Varoli
authors.forename: Piero
authors.initials: P
authors.lastname: Angeli
authors.forename: Michela
authors.initials: M
authors.lastname: Buccioni
authors.forename: Silvia
authors.initials: S
authors.lastname: Burnelli
authors.forename: Nicola
authors.initials: N
authors.lastname: Fazio
authors.forename: Gabriella
authors.initials: G
authors.lastname: Marucci
authors.forename: Maurizio
authors.initials: M
authors.lastname: Recanatini
authors.forename: Santi
authors.initials: S
authors.lastname: Spampinato
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006168:Guinea Pigs; D018727:Muscarinic Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011817:Rabbits; D043588:Receptor, Muscarinic M4 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D018727:Muscarinic Antagonists; D010880:Piperidines; D043588:Receptor, Muscarinic M4; C004858:diphenidol