PYRIDOBENZOXAZEPINE AND PYRIDOBENZOTHIAZEPINE DERIVATIVES AS POTENTIAL CENTRAL-NERVOUS-SYSTEM AGENTS - SYNTHESIS AND NEUROCHEMICAL STUDY

In order to characterize the pharmacological profile of-the different chemical classes of pyridobenzazepine derivatives, a series of N-methylpiperazinopyrido[1,4]- and -[1,5]- benzoxa- and benzothiazepine derivatives were prepared. The affinities-for D-2, D-1, 5-HT2, and cholinergic (M)receptors were measured. In comparison to dibenzazepine reference compounds, a strong decrease of the affinities was observed, less pronounced, however, for the substituted analogues. Oxazepine and thiazepine analogues like clozapine (except 8-chloro-6-(4-methylpiperazin-1-yl)pyrido[2,3-b] [1,4]-benzoxazepine (9) and 8-chloro-6-(4-methylpiperazin-1-yl)pyrido[2,3-b][1,4]-benzothiazepine (11)) were found to be inactive against apomorphine stereotypies. In the open-field test in rats, different molecules showed-a high disinhibitory activity as observed with anxiolytic drugs. Moreover, 8-chloro-5-(4-methylpiperazin-1-yl)pyrido [2,3-b] [1,5]benzoxazepine (14) presented a clozapine-like profile that was confirmed in the behavioral model in dogs and showed most of the behavioral characteristics described for antipsychotic drugs. Its neurochemical profile, in particular the 5-HT2/D-2 ratio was also compatible with atypical antipsychotic activity.