Anorectic, thermogenic and anti-obesity activity of a selective orexin-1 receptor antagonist in ob/ob mice

Regul Pept. 2002 Mar 15;104(1-3):153-9. doi: 10.1016/s0167-0115(01)00358-5.


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.

MeSH terms

  • Adipose Tissue, Brown / drug effects*
  • Animals
  • Benzoxazoles / pharmacology*
  • Body Composition / drug effects
  • Body Weight / drug effects
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / drug therapy
  • Disease Models, Animal
  • Eating / drug effects
  • Energy Metabolism / drug effects
  • Female
  • Insulin / blood
  • Mice
  • Mice, Inbred Strains
  • Naphthyridines
  • Obesity / blood
  • Obesity / genetics
  • Obesity / physiopathology*
  • Orexin Receptors
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / drug effects
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide / antagonists & inhibitors*
  • Receptors, Neuropeptide / biosynthesis
  • Receptors, Neuropeptide / genetics
  • Receptors, Neuropeptide / metabolism
  • Urea / analogs & derivatives
  • Urea / pharmacology*


  • 1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea
  • Benzoxazoles
  • Insulin
  • Naphthyridines
  • Orexin Receptors
  • RNA, Messenger
  • Receptors, G-Protein-Coupled
  • Receptors, Neuropeptide
  • Urea