Orexins and the treatment of obesity.
Orexin-A and -B are two peptides derived by proteolytic cleavage from a 130-amino acid precursor, prepro-orexin, which were recently isolated from the rat hypothalamus. Orexin-A is fully conserved across mammalian species, whilst rat and human orexin-B differ by two amino acids. These peptides bind to two Gq-coupled receptors, termed orexin-1 and orexin-2. The receptors are 64% homologous and highly conserved across species. Orexin-A is equipotent at orexin-1 and orexin-2 receptors, whilst orexin-B displays moderate (approximately 10 fold) selectivity for orexin-2 receptors. The distribution and pharmacology of the orexin peptides and their receptors indicate that they play a role in various regulatory systems including energy homeostasis and the regulation of feeding, the evidence for which is reviewed here.
Smart
Darren
D
Neurology CEDD, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. darren_2_smart@gsk.com
Haynes
Andrea C
AC
Williams
Gareth
G
Arch
Jonathan R S
JR
D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects / Q000502:physiology; D002352:Carrier Proteins / Q000494:pharmacology / Q000502:physiology*; D004435:Eating / Q000187:drug effects / Q000502:physiology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides / Q000494:pharmacology / Q000502:physiology*; D009765:Obesity / Q000188:drug therapy / Q000503:physiopathology*; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D002352:Carrier Proteins; C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009287:Naphthyridines; D009479:Neuropeptides; D064446:Orexin Receptors; D000068797:Orexins; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea