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Novel atypical antipsychotic agents: rational design, an efficient palladium-catalyzed route, and pharmacological
Giuseppe Campiani1, Stefania Butini, Caterina Fattorusso
1Dipartimento Farmaco Chimico Tecnologico, Via Aldo Moro, and European Research Centre for Drug Discovery and Development, Università di Siena, 53100 Siena, Italy. campiani@unisi.it
Abstract:
Using rational drug design to develop atypical antipsychotic drug candidates, we generated novel and metabolically stable pyrrolobenzazepines with an optimized pK(i) 5-HT(2A)/D(2) ratio. 5a, obtained by a new palladium-catalyzed three-step synthesis, was selected for further pharmacological and biochemical investigations and showed atypical antipsychotic properties in vivo. 5a was active on conditioned avoidance response at 0.56 mg/kg, it had low cataleptic potential and proved to be better than ST1899, clozapine, and olanzapine, representing a new clinical candidate.
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