Antagonists of the orexin receptors

Orexin-A and orexin-B are neuropeptides that are produced by neurons in the lateral hypothalamus. These neuropeptides bind and activate two closely related G-protein-coupled receptors, orexin-1 and orexin-2, and are involved in a variety of biological functions, including feeding, sleep-wake cycle, regulation of gastric acid secretion and reward seeking. Orexin-1 receptor agonists are shown to have antinociceptive activity, whilst orexin-1 receptor antagonists reverse both orexin-A and fasting-induced food intake. Mutant and non-functional orexin-2 receptor is linked to canine and some cases of human narcolepsy. Orexin-A was undetectable in the cerebrospinal fluid of 32 out of 38 narcoleptic patients, but readily detected in normal control individuals. These findings indicate that orexin receptor antagonists could be useful for the treatment of obesity, diabetes and sleep disorders. This review covers patent literature published during the period 1999 - 2005 on orexin-1 and orexin-2 receptor antagonists, together with some recent literature covering orexin receptor agonists.