Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice.
A single dose of the orexin-1 (OX1) receptor antagonist 1-(2-methylbenzoxazol-6-yl)-3-[1,5] naphthyridin-4-yl urea hydrochloride (SB-334867-A) reduces orexin-A-induced feeding and natural feeding in Sprague Dawley rats. In this study, the anti-obesity effects of SB-334867-A were determined in genetically obese (ob/ob) mice dosed with SB-334867-A (30 mg/kg, i.p.) once daily for 7 days, and then twice daily for a further 7 days. SB-334867-A reduced cumulative food intake and body weight gain over 14 days. Total fat mass gain, determined by Dual Emission X-ray Absorptiometry, was reduced, while gain in fat-free mass was unchanged. Fasting (5 h) blood glucose was also reduced at the end of the study, with a trend to reduced plasma insulin. Interscapular brown adipose tissue (BAT) weight was reduced, the tissue was noticeably darker in colour and quantitative PCR (TaqMan) analysis of this tissue showed a trend to an increase in uncoupling protein-1 mRNA expression, suggesting that SB-334867-A might stimulate thermogenesis. This was confirmed in a separate study in which a single dose of SB-334867-A (30 mg/kg, i.p.) increased metabolic rate over 4 h in ob/ob mice. OX1 receptor mRNA was detected in BAT, and its expression was increased by 58% by treatment with SB-334867-A. This is the first demonstration that OX1 receptor antagonists have potential as both anti-obesity and anti-diabetic agents.
Haynes
Andrea C
AC
GlaxoSmithKline, Third Avenue, Harlow, Essex, CM19 5AW, UK. Andrea_Haynes-1@gsk.com
Chapman
Helen
H
Taylor
Colleen
C
Moore
Gary B T
GB
Cawthorne
Michael A
MA
Tadayyon
Mohammad
M
Clapham
John C
JC
Arch
Jonathan R S
JR
D002001:Adipose Tissue, Brown / Q000187:drug effects*; D000818:Animals; D001583:Benzoxazoles / Q000494:pharmacology*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D007328:Insulin / Q000097:blood; D051379:Mice; D008815:Mice, Inbred Strains; D009287:Naphthyridines; D009765:Obesity / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D064446:Orexin Receptors; D012333:RNA, Messenger / Q000096:biosynthesis / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000494:pharmacology*
C420062:1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea; D001583:Benzoxazoles; D007328:Insulin; D009287:Naphthyridines; D064446:Orexin Receptors; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D014508:Urea