EXAMINATION OF THE D(2) 5-HT(2) AFFINITY RATIOS OF RESOLVED 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 6,7,8,9,10-hexahydro-7,10-iminocy clohept[b]indoles were obtained by the resolution of ,6,7,8,9,10-hexah ydro-7,10-iminocyclohept[b]indole and ,6,7,8,9,10-hexahydro-7,10-imino cyclohept[b]indole followed by N-alkylation. These, as well as the rac emates, were evaluated for their affinity for the 5-HT2 and D2 recepto rs. Those compounds possessing the 7S,10R stereochemistry were consist ently recognized by the 5-HT2 and D2 receptors as the eutomer. ,7,8,9, 10-hexahydro-7S,10R-iminocyclohept[b]indole [(7S,10R)-8] had the highe st affinity for the 5-HT2 receptor (K(i) = 0.80 nM), while its distome r (7R,10S)-8 was the most selective member of this class of bridged ga mma-carbolines (D2/5-HT2 = 562). Incorporation of a benzoyl or isoster ic 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.