Benz[f]isoquinoline Analogues as High-Affinity Sigma Ligands

J Med Chem. 1992 May 29;35(11):2025-33. doi: 10.1021/jm00089a012.

Abstract

This paper describes the synthesis of some conformationally restricted 4-phenylpiperidine analogues and their affinities for the guinea pig cerebellum sigma recognition site ([3H]-DTG) and the rat striatum dopamine D2 receptor ([3H]-(-)-sulpiride) in order to develop potent selective sigma ligands as tools in the investigation of this site in psychosis. It was found that both hexa- and octahydrobenz[f]isoquinolines with lipophilic N-substituents had high affinities for the sigma site. Notably, trans-3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline (26) had an affinity of 0.25 nM making it the highest affinity sigma ligand reported to date. Moreover, it is at least 10,000-fold selective over the D2 receptor and could prove to be a valuable tool in the study of sigma sites. Other analogues such as 1H-indeno[2,1-c]pyridines and 1H-benzo[3,4]cyclohepta[1,2-c]pyridines also displayed high sigma site affinity.

MeSH terms

  • Animals
  • Cerebellum / metabolism
  • Chemical Phenomena
  • Chemistry, Physical
  • Guinea Pigs
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / metabolism
  • Isoquinolines / pharmacology
  • Male
  • Molecular Conformation
  • Molecular Structure
  • Piperidines / chemistry*
  • Rats
  • Rats, Inbred Strains
  • Receptors, Dopamine / metabolism*
  • Receptors, Dopamine D2
  • Receptors, Opioid / metabolism*
  • Receptors, sigma
  • Structure-Activity Relationship
  • X-Ray Diffraction

Substances

  • Isoquinolines
  • Piperidines
  • Receptors, Dopamine
  • Receptors, Dopamine D2
  • Receptors, Opioid
  • Receptors, sigma
  • 3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz(f)isoquinoline
  • 4-phenylpiperidine