Analogues of the Muscarinic Agent 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane]: Synthesis and Pharmacology

J Med Chem. 1992 May 1;35(9):1541-50. doi: 10.1021/jm00087a007.

Abstract

A number of tetrahydrofuran analogues of 2'-methylspiro[1-azabicyclo[2.2.2]octane-3,4'-[1,3]dioxolane] (1) have been prepared with the aim to obtain information about the relative importance of each of the oxygens in 1 for efficacy and for selectivity. In addition, the dimethyl and desmethyl analogues of 1 were prepared. The new compounds were compared to cis- and trans-1 with regard to their ability to displace (-)-[3H]-3-quinuclidinyl benzilate ((-)-[3H]QNB) from muscarinic receptors in cerebral cortex, heart, parotid gland, and urinary bladder from guinea pigs. Functional studies were made on isolated guinea pig bladder and ileum. The new compounds exhibited both lower affinity and efficacy than cis-1. A conformational study was performed, and the effects of steric and electronic factors on the biological activity of the compounds are discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bridged Bicyclo Compounds / chemical synthesis*
  • Bridged Bicyclo Compounds / pharmacology
  • Dioxolanes / chemical synthesis*
  • Dioxolanes / pharmacology
  • Guinea Pigs
  • Ileum / drug effects
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Quinuclidinyl Benzilate / metabolism
  • Receptors, Muscarinic / drug effects*
  • Receptors, Muscarinic / metabolism
  • Spiro Compounds*
  • Stereoisomerism
  • Substrate Specificity
  • Urinary Bladder / drug effects

Substances

  • Bridged Bicyclo Compounds
  • Dioxolanes
  • Receptors, Muscarinic
  • Spiro Compounds
  • 2'-methylspiro-(1-azabicyclo(2.2.2.)octane-3,4'-(1,3)-dioxolane)
  • Quinuclidinyl Benzilate