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Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders

2011; Elsevier BV; Volume: 21; Issue: 18 Linguagem: Inglês

10.1016/j.bmcl.2011.06.086

1464-3405

Romano Di Fabio, Annalisa Pellacani, Stefania Faedo, Adelheid Roth, Laura Piccoli, Philip Gerrard, Rod A. Porter, Christopher N. Johnson, Kevin M. Thewlis, Daniele Donati, Luigi Stasi, Simone Spada, Geoffrey Stemp, David J. Nash, Clive L. Branch, Leanda Kindon, Mario Massagrande, Alessandro Poffe, Simone Braggio, Elisabetta Chiarparin, Carla Marchioro, Emiliangelo Ratti, Mauro Corsi,

Circadian rhythm and melatonin

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.