New Pyridobenzoxazepine Derivatives Derived from 5-(4-Methylpiperazin-1-yl)-8-chloro-pyrido[2,3-<i>b</i>][1,5]benzoxazepine (JL13): Chemical Synthesis and Pharmacological Evaluation

A series of new pyridobenzoxazepine derivatives with various heterocyclic amine side chains were synthesized to explore two main parameters related to the distal basic nitrogen. These compounds were tested for their affinity for dopamine D_2L and D₄, serotonin 5-HT_1A and 5-HT_2A, and adrenergic α_2A receptors in comparison with 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido­[2,3-<i>b</i>]­[1,5]­benzoxazepine, JL13 (<b>1</b>), and other diarylazepine derivatives. In terms of multireceptor target strategy, <b>2</b> and <b>5</b> present the most promising <i>in vitro</i> binding profile. Bulky, polar, and more flexible side chains are not favorable in this context. Compounds <b>2</b> and <b>5</b> were tested in adult rats to evaluate their long-term effects on dopamine and serotonin receptors density in different brain areas. Similar to <b>1</b> and other second-generation antipsychotic drugs, repeated treatment with <b>2</b> significantly increased D₁ and D₄ receptors in nucleus accumbens and caudate putamen and D₂ receptors in medial prefrontal cortex and hippocampus, while <b>5</b> significantly increased D₂ and D₄ receptors in nucleus accumbens. In addition, <b>2</b> increased 5-HT_1A and decreased 5-HT_2A receptors in cerebral cortex. In contrast, <b>5</b> did not alter levels of any 5-HT receptor subtype in any brain region examined. These results encourage further development of <b>2</b> as a novel second-generation antipsychotic agent