title: 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.
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.
authors.affiliation: Department of Medicinal Chemistry, Scios Nova Inc., Baltimore, Maryland 21224-6522.
authors.forename: R E
authors.initials: RE
authors.lastname: Mewshaw
authors.forename: M E
authors.initials: ME
authors.lastname: Abreu
authors.forename: L S
authors.initials: LS
authors.lastname: Silverman
authors.forename: R M
authors.initials: RM
authors.lastname: Mathew
authors.forename: C W
authors.initials: CW
authors.lastname: Tiffany
authors.forename: M A
authors.initials: MA
authors.lastname: Bailey
authors.forename: E W
authors.initials: EW
authors.lastname: Karbon
authors.forename: J W
authors.initials: JW
authors.lastname: Ferkany
authors.forename: C
authors.initials: C
authors.lastname: Kaiser
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D014150:Antipsychotic Agents; D007211:Indoles; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin