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

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 an the racemates, were evaluated for their affinity for the 5-HT 2 and D 2 receptors. Those compounds possessing the 7S,10R stereochemistry were consistently recognized by the 5-HT 2 and D 2 receptors as the eutomer. 2-Fluoro-11-[4-(4-fluorophenyl)-4-oxobutyl]-5,6,7,8,9,10-hexahydro-7S,10R-iminocyclohept[b]indole [(7S,10R)-8] had the highest affinity for the 5-HT 2 receptor , while its distomer (7R,10S)-8 was the most selective member of this class of bridged γ-carbolines (D 2 /5-HT 2 =562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a brigded γ-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT 2 and D 2 receptors