Synthesis and Preliminary Pharmacological Evaluation of 4′-Arylalkyl Analogues of Clozapine. II. Effect of the Nature and Length of the Linker

We report the synthesis of a second generation of tricyclic analogues of clozapine, investigating the length and nature of the chain between an ionizable nitrogen atom at physiological pH and the introduced aryl moiety. The chemistry, structural characterization, and pharmacological evaluation of this series of 4'-arylalkyl analogues of clozapine are described. Preliminary findings on the effects on activity of the nature and length of the linker, degree of unsaturation, and type of aryl moiety on blockade of dopamine D4 and serotonin 5-HT2A receptors are discussed and animal behavioural data for key compounds presented.