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[摘要]：A review. Orexin/hypocretin neuropeptides (orexin-A or hypocretin1 and orexin-B or hypocretin2) are peptides discovered and published in 1998 as the outcome of methodical deorphanization programs focusing on brain orphan G-protein-coupled receptors (GPCR). Orexins/hypocretins bind to two receptors (orexin1/OX1 or HCRT1 and orexin2/OX2 or HCRT2 receptors) and are proteolytically derived from a single precursor peptide in a discrete population of neurons of the perifornical area of the lateral hypothalamus. OX1 receptors have preferential affinity for orexin-A, whereas OX2 receptors do not discriminate between both neuropeptides in vitro. OX1 or OX2 activation produces intracellular Ca2+ increases via functional coupling involving a Gq or Go mechanism of transduction. This ultimately results in slow membrane depolarization and in neuronal activation found to involve different ionic conductance in various brain regions in the rat, such as potassium conductance in the locus coeruleus or calcium current in the tuberomammilary nucleus. Manipulation of the orexin system using brain-penetrant orexin receptor antagonists or inverse agonists will probably prove therapeutically useful in the treatment of those medical and psychiatric conditions assocd. with disturbed vigilance. Orexin circuitry may indeed be disturbed under states such as sleep loss, night or shift work, jet lag, or even aging. A major advantage of brain-penetrant receptor ligands over engineered genetic modifications is their transient mode of action, allowing recovery to natural orexin function. This property is of major pharmacol. interest for scientific and therapeutic innovation in this field. Hopefully, many novel orexin receptor ligands of second or third generation will emerge from the current medicinal chem. programs and will further contribute to the understanding of the physiol. and pathophysiol. roles of endogenous orexins. |
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