Cyclohexylmethylpiperidinyltriphenylpropioamide: A Selective Muscarinic M(3) Antagonist Discriminating Against the Other Receptor Subtypes

J Med Chem. 2002 Feb 14;45(4):984-7. doi: 10.1021/jm010480k.

Abstract

To discover a highly selective M(3) antagonist, a combinatorial library was prepared. The library was designed to identify a novel structural class of M(3) antagonists by exploring the spatial arrangement of the pharmacophores in known M(3) antagonists. After the evaluation of 1000 library members, a potent M(3) antagonist, 14a (K(i) = 0.31 nM), with novel structural features was identified. Compound 14a showed high selectivity for M(3) receptors over the other muscarinic receptor subtypes (M(1)/M(3) = 380-fold, M(2)/M(3) = 98-fold, M(4)/M(3) = 45-fold, M(5)/M(3) = 120-fold).

MeSH terms

  • Acetylcholine
  • Animals
  • Bradycardia / chemically induced
  • Bradycardia / physiopathology
  • Bronchoconstriction / drug effects
  • CHO Cells
  • Carbachol
  • Cholinergic Agents
  • Combinatorial Chemistry Techniques
  • Cricetinae
  • Dipeptides / chemical synthesis*
  • Dipeptides / chemistry
  • Dipeptides / pharmacology
  • Heart Atria / drug effects
  • Humans
  • In Vitro Techniques
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / chemistry
  • Muscarinic Antagonists / metabolism
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / metabolism
  • Piperidines / pharmacology
  • Rats
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship

Substances

  • Cholinergic Agents
  • Dipeptides
  • Muscarinic Antagonists
  • N-(2-(3-((1-(cyclohexylmethyl)-3-piperidinyl)methylamino)-3-oxopropyl)amino-2-oxoethyl)-3,3,3-triphenylpropionamide
  • Piperidines
  • Receptor, Muscarinic M3
  • Receptors, Muscarinic
  • Carbachol
  • Acetylcholine