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Abstract: The hypothalamic peptides orexin-A and orexin-B are potent agonists of two G-protein coupled receptors, namely the OX1 and the OX2 receptor. These receptors are widely distributed, though differentially, in the rat brain. In particular, the OX1 receptor is highly expressed throughout the hypothalamus, whilst the OX2 receptor is mainly located in the ventral posterior nucleus. A large body of compelling evidence, both pre-clinical and clinical, suggests that the orexin system is profoundly implicated in sleep disorders. In particular, modulation of the orexin receptors activation by appropriate antagonists was proven to be an efficacious strategy for the treatment of insomnia in man. A novel, drug-like bis-amido piperidine derivative was identified as potent dual OX1 and OX2 receptor antagonists, highly effective in a pre-clinical model of sleep. [Copyright &y& Elsevier]

Abstract: A novel imidazobenzazepine template (5a) with potent dual H1/5-HT2A antagonist activity was identified. Application of a zwitterionic approach to this poorly selective and poorly developable starting point successfully delivered a class of high quality leads, 3-[4-(3-R1-2-R-5H-imidazo[1,2-b][2]benzazepin-11-yl)-1-piperazinyl]-2,2-dimethylpropanoic acids (e.g., 9, 19, 20, and 21), characterized by potent and balanced H1/5-HT2A receptor antagonist activities and good developability profiles. [ABSTRACT FROM AUTHOR]