Synthesis and pharmacological investigation of new chiral muscarinic antagonists

Farmaco. 1995 Jan;50(1):21-7.

Abstract

The two pairs of enantiomers of isoxazolidin-3-ones 3 and 4 were synthesized by means of Lipase PS-catalyzed hydrolyses of suitable racemic butyrates. The same butyrates were also employed as key intermediates in the preparation of racemic 3 and 4. The antimuscarinic potency of the new compounds was assayed in two in vitro functional tests. The eutomers (-)-3 and (-)-4 share the same stereochemistry (5R) of the most potent enantiomer of "azamuscarone" 2, a structurally related muscarinic agonist. Such a spatial arrangement around the chiral center of 2-4, coupled with the low values of eudismic ratio, represents an anomaly among the chiral muscarinic ligands. This anomaly was accounted for by the absence of a chiral center at C-2, a position whose configuration is crucial in determining the high enantioselectivity of muscarinic agonists and antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Guinea Pigs
  • In Vitro Techniques
  • Male
  • Muscarinic Antagonists / chemical synthesis*
  • Muscarinic Antagonists / pharmacology
  • Rats
  • Rats, Wistar
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Muscarinic Antagonists