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

Abstract

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.

• Authors: Andrea C Haynes, Helen Chapman, Colleen Taylor, Gary B T Moore, Michael A Cawthorne, Mohammad Tadayyon, John C Clapham, Jonathan R S Arch
• Journal: Regulatory peptides (Regul Pept) Vol. 104 Issue 1-3 Pg. 153-9 (Mar 15 2002) ISSN: 0167-0115 [Print] Netherlands
• PMID: 11830290 (Publication Type: Journal Article)

Chemical References

• 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

Topics

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