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 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.
Mewshaw
R E
RE
Department of Medicinal Chemistry, Scios Nova Inc., Baltimore, Maryland 21224-6522.
Abreu
M E
ME
Silverman
L S
LS
Mathew
R M
RM
Tiffany
C W
CW
Bailey
M A
MA
Karbon
E W
EW
Ferkany
J W
JW
Kaiser
C
C
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
D014150:Antipsychotic Agents; D007211:Indoles; D017448:Receptors, Dopamine D2; D011985:Receptors, Serotonin