BRIDGED GAMMA-CARBOLINES AND DERIVATIVES POSSESSING SELECTIVE AND COMBINED AFFINITY FOR 5-HT2 AND D(2)-RECEPTORS

A series of 6,7,8,9,10-hexahydro-7,10-iminocyclohept[b]indoles and ,10 ,11-hexahydro-7,-11-imino-5H-cyclooct[b]indoles was prepared. Structur al modifications of the lead compound, ,6,7,8,9,10-hexahydro-7,10-imin ocyclohept[b]indole (5, K(i) = 0.82 nM vs [H-3]ketanserin) enabled the identification of the functionality necessary for high affinity at se rotonin 5-HT2 and dopamine D2 receptors in ligand binding studies. The indole ring, as well as the benzoyl or isosteric benzisoxazole moiety , were essential for high affinity. Variations of the length of the si de chains resulted in ligands having either selective affinity for the 5-HT2 receptor or a combination of 5-HT2 and D2 affinity. In vivo bin ding studies were performed on selected members in this series. The mo st potent member, 6,7,8,9,-10-hexahydro-7,10-iminocyclohept[b]indole ( 36) had an ED50 of <1 mg/kg at the 5-HT2 and D2 receptors following or al administration.