Comparative study of typical neuroleptics, clozapine and newly synthesized clozapine-analogues: correlations between neurochemistry and behaviour.

While neuroleptic therapy with classical compounds has frequently been associated with extrapyramidal side effects, clozapine has revealed an interesting antipsychotic profile without producing any clearcut motor side effects. However, some adverse reactions remained that stimulated the search for improved antipsychotic agents. The aim of this study was to characterize the behavioural and neurochemical profiles of typical neuroleptics (chlorpromazine, haloperidol), clozapine, and four newly synthesized clozapine-analogues. Affinity for dopaminergic (D1,D2), serotonergic (5-HT(2)) and cholinergic (muscarinic) receptors were measured and the ratios of these different binding affinities were determined and correlated with the behavioural effects of the drugs in a complex temporal regulation task in the dog. The four clozapine-analogues showed most of the behavioural characteristics previously described for neuroleptics and their neurochemical profile, particularly their 5-HT(2)/D2 pKi ratio, was compatible with an atypical antipsychotic effect. Among these drugs, JL5 and JL13 showed a high degree of similarity with clozapine. Like clozapine, they did not induce catalepsy and stereotypy/hyperkinesia. Moreover, other motor effects were also reduced (ataxia, akinesia, dystony). and tremor and sialorrhea were completely absent with these two molecules.