Azabicycloalkanes as analgetics. 3. Structure-activity relationships of 1-phenyl-6-azabicyclo[3.2.1]octanes and absolute stereochemistry of (+)-1-(3-hydroxyphenyl)-6-methyl-6-azabicyclo[3.2.1]octane and its 7-endo-methyl derivative

J Med Chem. 1977 Feb;20(2):221-8. doi: 10.1021/jm00212a007.

Abstract

A series of 53 1-phenyl-6-azabicyclo[3.2.1]octanes (1) has been tested for their analgetic and narcotic antagonist activities. Structure-activity relationships were investigated by varying the structural parameters. The most interesting compound in this series, the 1-(3-hydroxphenyl)-6,7-dimethyl derivative 8, shows the profile of a well-balanced antagonist-analgesic agent with a very mild physical dependence capacity. The absolute stereochemistry of its active enantiomer [(+)8] was established by the x-ray study and the chemical transformation to the phenylmorphan [(+)-II]. (+)-8 was stereochemically correlated also with the active enantiomer of the 7-demethyl derivatives [(+)-7] by chemical transformation and CD measurement. Certain structural and stereochemical correlations between these compounds (7 and 8) and other known antagonist-analgetics are discussed.

Publication types

  • Comparative Study

MeSH terms

  • Analgesics*
  • Animals
  • Bridged Bicyclo Compounds / pharmacology*
  • Bridged Bicyclo Compounds / toxicity
  • Bridged-Ring Compounds / pharmacology*
  • Haplorhini
  • Humans
  • Lethal Dose 50
  • Macaca mulatta
  • Molecular Conformation
  • Nalorphine / pharmacology
  • Narcotic Antagonists
  • Rabbits
  • Stereoisomerism
  • Structure-Activity Relationship
  • Substance Withdrawal Syndrome / chemically induced
  • Substance-Related Disorders / etiology
  • X-Ray Diffraction

Substances

  • Analgesics
  • Bridged Bicyclo Compounds
  • Bridged-Ring Compounds
  • Narcotic Antagonists
  • Nalorphine