Conformationally restricted butyrophenones with mixed dopaminergic (D-2) and serotoninergic (5-MT2A) affinities. Synthesis of 5-aminoethyl- and 6-aminomethyl-4-oxotetrahydroindoles as potential atypical antipsychotics

We describe the synthesis of 5-aminoethyl- and 6-aminomethyl-4-oxotetrahydr oindoles as butyrophenone derivatives in the indole series, as potential at ypical antipsychotics. The affinities of these compounds for serotonin (5-H T2A) and dopamine (D-2) receptors were evaluated in vitro. The ratios of pK (i)'s for 5-HT2A/D-2 receptors may be useful for rapid screening of new com pounds and assessing potential induction of extrapyramidal symptoms; ratio values greater than or equal to 1.12 (Meltzer's ratio) are predictive of an atypical antipsychotic profile. Compounds 26e (QF 0408B) and 26f (QF 0409B ) showed high affinity for both D-2 and 5-HT2A receptors, and their Meltzer 's ratios were 1.32 and 1.17 respectively, while haloperidol showed a ratio of 0.93.