Synthesis and pharmacological profile of a series of 1-substituted-2-carbonyl derivatives of Diphenidol: novel M4 muscarinic receptor antagonists

Med Chem. 2008 Mar;4(2):121-8. doi: 10.2174/157340608783789211.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Guinea Pigs
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / pharmacology
  • Piperidines / chemical synthesis
  • Piperidines / chemistry*
  • Piperidines / pharmacology*
  • Rabbits
  • Receptor, Muscarinic M4 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Muscarinic Antagonists
  • Piperidines
  • Receptor, Muscarinic M4
  • diphenidol