TY - JOUR
T1 - Examination of the D2/5-HT2 Affinity Ratios of Resolved 5,6,7,8,9,10-Hexahydro-7,10-iminocyclohept[b]indoles
T2 - An Enantioselective Approach toward the Design of Potential Atypical Antipsychotics
AU - Mewshaw, Richard E.
AU - Abreu, Mary E.
AU - Silverman, Lisa S.
AU - Mathew, Rose M.
AU - Tiffany, Carol W.
AU - Bailey, Michael A.
AU - Karbon, E. William
AU - Ferkany, John W.
AU - Kaiser, Carl
PY - 1993/1/1
Y1 - 1993/1/1
N2 - Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[6]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,10R-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 γ-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged γ-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.
AB - Enantiomers of several N-substituted 5,6,7,8,9,10-hexahydro-7,10-iminocyclohept[6]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,10R-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 γ-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isosteric benzisoxazole moiety tethered by a four-carbon spacer to a bridged γ-carboline nucleus, possessing the 7S,10R absolute configuration, produced high affinity ligands for the 5-HT2 and D2 receptors.
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U2 - 10.1021/jm00073a005
DO - 10.1021/jm00073a005
M3 - Article
C2 - 7901415
AN - SCOPUS:0027340565
SN - 0022-2623
VL - 36
SP - 3073
EP - 3076
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 21
ER -