Synthesis, muscarinic blocking activity and molecular modeling studies of 4-DAMP-related compounds

Bioorg Med Chem. 1995 Mar;3(3):267-77. doi: 10.1016/0968-0896(95)00021-8.

Abstract

A number of compounds structurally related to 4-DAMP (1) were synthesized and a single crystal X-ray structural study on a representative member of this series was carried out. All the compounds were tested for the antagonist activity in isolated guinea pig atria (M2 muscarinic receptors) and ileum (M3 muscarinic receptors). Affinity values (pA2) for the muscarinic receptor subtypes ranged from 5.39 to 9.71 (M2) and from 5.68 to 9.92 (M3), depending on different structural features of the compounds. A molecular modeling study was performed, with the aim of rationalizing the affinity data for both M2 and M3 muscarinic receptor subtypes. The presence in the series of two highly active, structurally constrained derivatives allowed us to define two different pharmacophoric frames on which all the compounds could be fitted in a satisfactory manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Crystallography, X-Ray
  • Guinea Pigs
  • Ileum / drug effects
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Muscarinic Antagonists* / chemical synthesis*
  • Muscarinic Antagonists* / chemistry
  • Muscarinic Antagonists* / pharmacology*
  • Myocardium / metabolism
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Receptors, Muscarinic / metabolism

Substances

  • Muscarinic Antagonists
  • Piperidines
  • Receptors, Muscarinic
  • 4-diphenylacetoxy-1,1-dimethylpiperidinium