Synthesis and Affinities for Dopamine (D_2) and 5-Hydroxytryptamine (5-HT_<2A>) Receptors of 1-(Benzoylpropyl)-4-(1-oxocycloalkyl-2-ethyl)-piperazines as Cyclic Butyrophenone Derivatives

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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 (D_2) 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>/D_2 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.
公益社団法人日本薬学会の論文
1996-03-15