NEW PYRIDOBENZODIAZEPINE DERIVATIVES AS POTENTIAL ANTIPSYCHOTICS - SYNTHESIS AND NEUROCHEMICAL STUDY

The discovery of a new, safe, atypical antipsychotic remains an import ant challenge. To achieve this goal, a series of N-methylpiperazinopyr ido[2,3-b][1,4]- and -[1,5]- and -pyrido[4,3-b][1,4]- and -[1,5]-benzo diazepines were synthesized. The dopaminergic (D1, D2), serotonergic ( 5-HT2), and cholinergic (M) affinities, frequently remarked in the act ion mechanisms of antipsychotic drugs, were determined using their res pective in vitro receptor binding assays. All affinities were reduced for each compound. Optimal substituents were found to be in the 2- or 8-position for the retention of affinities, while substitution at the 5-position by acyl or alkyl groups dramatically diminished binding aff inities. Pyridobenzodiazepine derivatives, such as clozapine, were fou nd to be inactive or only weakly effective against apomorphine-mediate d stereotypes in rats. In an original and complex behavioral model dev eloped in dogs and successfully used to differentiate distinct classes of psychotropic drugs and to discriminate between typical and atypica l neuroleptic drugs, -piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepin e (9), -piperazinyl)-11H-pyrido[2,3-b][1,4]benzodiazepine (12), and pi per-azinyl)-11H-pyrido[2,3-b][1,5]benzodiazepine (16) showed most of t he behavioral characteristics previously described for neuroleptics. T heir neurochemical profiles, particularly their 5-HT2/D2 pK(i) ratios, were compatible with an atypical antipsychotic effect. These compound s were selected for further investigation. The proposed modulations co uld lead to new possibilities for the pharmacochemistry of diarylazepi nes.