A selective orexin-1 receptor antagonist reduces food consumption in male and female rats

A variety of evidence implicates the orexins, especially orexin-A, in the r egulation of food intake, but it has not been established whether this effe ct is mediated by the orexin-1 or orexin-2 receptor. In the present study, a selective orexin-1 receptor antagonist, 1-(2-methylbenzoxazol-6-yl)-3-[1. 5]naphthyridin-4-yl urea hydrochloride (SB-334867-A), was administered intr aperitoneally to rats under various conditions, and food consumption was su bsequently measured over 24 h. In male rats, a single dose of SB-334867-A ( 30 mg/kg, i.p.) given during the light phase reduced both orexin-A-induced food intake (7 nmol. i.c.v.) and feeding stimulated by an overnight fast fo r 4 h. When given at the start of the dark phase, food consumption was redu ced in both male and female rats over 24 h. Daily injections at the start o f the dark phase for 3 days reduced natural feeding in male rats over 24 h on days one and three. These findings demonstrate direct inhibition of orex in-A induced food intake with a selective orexin-1 receptor antagonist. Fur thermore, the suppression of nocturnal feeding and food intake stimulated b y an overnight fast supports other evidence that orexin-A is involved in th e regulation of natural feeding and suggests that orexin-1 receptor antagon ists could be useful in the treatment of obesity. (C) 2000 Elsevier Science B.V. All rights reserved.