Examination of the D2/5-HT2 affinity ratios of resolved 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles: an enantioselective approach toward the design of potential atypical antipsychotics

J Med Chem. 1993 Oct 15;36(21):3073-6. doi: 10.1021/jm00073a005.

Abstract

Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles were obtained by the resolution of 2-fluoro-5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole and 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indole followed by N-alkylation. These, as well as the racemates, were evaluated for their affinity for the 5-HT2 and D2 receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT2 and D2 receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10 R- iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT2 receptor (Ki = 0.80 nM), while its distomer (7R,10S)-8 was the most selective member of this class of bridged gamma-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged gamma-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.

MeSH terms

  • Antipsychotic Agents / chemical synthesis*
  • Antipsychotic Agents / chemistry
  • Antipsychotic Agents / pharmacology*
  • Chromatography, High Pressure Liquid
  • Crystallography, X-Ray
  • Drug Design
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Receptors, Dopamine D2 / drug effects*
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Serotonin / drug effects*
  • Receptors, Serotonin / metabolism
  • Stereoisomerism

Substances

  • Antipsychotic Agents
  • Indoles
  • Receptors, Dopamine D2
  • Receptors, Serotonin