Synthesis and Affinities for Dopamine (D₂) and 5-Hydroxytryptamine (5-HT_2A) Receptors of 1-(Benzoylpropyl)-4-(1-oxocycloalkyl-2-ethyl)-piperazines as Cyclic Butyrophenone Derivatives

Abstract

Starting from benzo- or thienocycloalkaneacetic acids, we have prepared a series of 1-(3-p-fluorobenzoylpropyl)-4-(1-oxo-benzo- or thienocycloalkyl-2-ethyl)piperazines 8a-e containing both semirigid and linear butyrophenones pharmacophores. The affinities of these compounds for dopamine (D₂) and 5-hydroxytryptamine (5-HT_2A) receptors were evaluated in vitro in receptor-binding assays and in functional experiments. The ratios of pK_i's for 5-HT_2A/D₂ receptors may be useful for rapid screening of new compounds and assessing potential induction of extrapyramidal symptoms; ratio values ≥-1.12 (Meltzer's ratio) are predictive of an atypical antipsychotic profile. The new molecules had a ratio in the range of 0.96-1.11 while haloperidol showed a ratio of 0.93. The 2-piperazinoethyl thiotetralone derivative 8d (QF 0506B) with a ratio of 1.11 was the most active compund.