Synthesis and preliminary pharmacological evaluation of 4'-arylalkyl analogues of clozapine. IV. the effects of aromaticity and isosteric replacement

We report the synthesis and preliminary pharmacological activity of a new series of tricyclic analogues of clozapine as potential antipsychotic agents for the treatment of schizophrenia. These compounds were designed based on a revised structural model, and investigate the length and nature of a designated linker ( alkyl and alkyloxy) and the nature of the introduced aryl group ( aromatic and heteroaromatic). The chemistry and structural characterization of this series of 4 -arylalkyl(oxy) analogues of clozapine are described. Preliminary results on the pharmacological effects of the selected linkers and introduced aryl groups on affinity for dopamine D-4 and serotonin 5-HT2A receptors are discussed. Psychosis-related animal behavioural data for promising compounds identified from the receptor binding screen are also presented.