Electrophilic gamma-lactone kappa-opioid receptor probes. Analogues of 2'-hydroxy-2-tetrahydrofurfuryl-5,9-dimethyl-6,7-benzomorphan diastereomers

J Med Chem. 1991 Aug;34(8):2438-44. doi: 10.1021/jm00112a019.

Abstract

Benzomorphans with an electrophilic group in the nitrogen substituent were prepared as potentially irreversible ligands for the kappa-opioid receptor. These were synthesized from products of the reaction of normetazocine with the enantiomers of 5-(iodomethyl)-gamma-butyrolactone (11). alpha-Methylene gamma-lactones 5 and 7 and endocyclic alpha,beta-unsaturated gamma-lactones 8 and 9 were prepared from the corresponding saturated gamma-lactones 13 and 23 possessing the "active" (1R,5R,9R)-benzomorphan stereochemistry. Only gamma-lactones 8, 9, 13, and 23, lacking the exocyclic methylene group, retain significant affinities for opioid receptor binding sites when compared with the reference compounds (2"S)-3 and (2"R)-3. As observed with these references compounds, greater binding affinity is also seen with gamma-lactone diastereomers having the 2"S stereochemistry in the nitrogen substituent. Although the gamma-lactones do not bind irreversibly in opioid receptor preparations, they do show kappa-receptor selectivities comparable to those observed for the reference compounds.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Benzomorphans / chemical synthesis*
  • Benzomorphans / chemistry
  • Benzomorphans / metabolism
  • Brain / metabolism
  • Cell Membrane / metabolism
  • Chemical Phenomena
  • Chemistry
  • Guinea Pigs
  • Molecular Conformation
  • Molecular Structure
  • Receptors, Opioid / metabolism*
  • Receptors, Opioid, kappa
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Benzomorphans
  • Receptors, Opioid
  • Receptors, Opioid, kappa
  • MR 2034