Enantioselectivity of muscarinic antagonists. Isomeric 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl]-1,3-oxathiolane methiodides

J Med Chem. 1988 Sep;31(9):1703-8. doi: 10.1021/jm00117a007.

Abstract

The four isomers of 2-cyclohexyl-2-phenyl-5-[(dimethylamino)methyl] -1,3-oxathiolane methiodide were prepared. Their absolute configuration was attributed by means of X-ray crystallography and circular dichroism. The compounds were tested on rat bladder and guinea pig ileum and heart, and their antimuscarinic potency was evaluated and expressed as pA2. The results show that the introduction of a chiral center into position 2 brings about a small but definite enantioselectivity on rat bladder and guinea pig ileum which is not seen for guinea pig heart. This supports the view that differences exist among the muscarinic receptors of these tissues (M2 receptors). Comparison of the absolute configuration of the antagonists studied in this and in the preceding paper2 and that of strictly related agonists supports the hypothesis of a common binding site for agonists and antagonists of this kind.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Atrial Function
  • Chemical Phenomena
  • Chemistry
  • Cyclohexanes / chemical synthesis
  • Cyclohexanes / pharmacology*
  • Guinea Pigs
  • Heart Rate / drug effects
  • Heterocyclic Compounds / chemical synthesis
  • Heterocyclic Compounds / pharmacology*
  • Ileum / physiology
  • Molecular Conformation
  • Muscarine / antagonists & inhibitors*
  • Muscle Contraction / drug effects
  • Myocardial Contraction / drug effects
  • Rats
  • Receptors, Muscarinic / drug effects
  • Receptors, Muscarinic / physiology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Thiophenes*
  • Urinary Bladder / physiology

Substances

  • Cyclohexanes
  • Heterocyclic Compounds
  • Receptors, Muscarinic
  • Thiophenes
  • 2,2-dicyclohexyl-5-((dimethylamino)methyl)-1,3-oxathiolane methiodide
  • Muscarine