Neuropeptide Y (NPY) is thought to play a key role in stimulating feeding, thus making NPY receptors attractive appetite suppressant drug targets for treating obesity. Because the orexigenic effects of NPY have been ascribed to actions at the NPY Y5 receptor, we have determined the role of this receptor in feeding in rats, using a small molecule antagonist of this receptor. NPY5RA-972 is a selective and potent (<10 nmol/l) NPY Y5 receptor antagonist. This compound is central nervous system (CNS) penetrant, and an oral dose of 10 mg/kg NPY5RA-972 to rats produced concentrations in cerebrospinal fluid that greatly exceeded the in vitro IC 50 (inhibitory concentration 50%). Indeed, at doses to rats as low as 1 mg/kg, NPY5RA-972 inhibited feeding induced by intracerebroventricular (ICV) administration of a selective NPY Y5 agonist ([cPP 1-7 ,NPY 19 -23 , Ala 31 ,Aib 32 ,Gln 34 ]-hPP). However, in the dose range 1-10 mg/kg, NPY5RA-972 had no significant effect on food intake in Wistar rats induced to feed by either ICV NPY or 24 h fasting or in free-feeding Wistar or obese Zucker rats. Chronic administration of NPY5RA-972 (10 mg/kg twice daily) had no effect on food intake or body weight in either free-feeding Wistar rats or dietary obese rats. These data indicate that NPY5RA-972 is a potent, selective, orally active, and CNS-penetrant antagonist of the NPY Y5 receptor that prevents feeding driven by activation of this receptor. The data obtained with this antagonist indicate that the NPY Y5 receptor is not a major regulator of feeding in the rat. Diabetes 51: 2441-2449, 2002 R esearch into appetite control during the past decade has been ignited by the discovery of leptin and fueled by the recognition of obesity as a widespread and rapidly growing disease (1). Leptin is a fat-derived hormone that signals energy (fat) storage levels to the hypothalamus. A number of previously identified (e.g., neuropeptide Y [NPY], melaninconcentrating hormone, corticotropin-releasing factor, galanin, neuromedin U, bombesin and pro-opiomelanocortin peptides) and newly discovered (agouti-related protein, cocaine and amphetamine-regulated transcript, urocortin, orexin, ghrelin) neuropeptides have become recognized as central nervous system (CNS) targets of leptin action (2-5). Many of these peptides are known to influence feeding in experimental species, and their receptors have been proposed as possible targets for appetite suppressant drugs. Corroborative evidence supporting these hypotheses from human (6,7) and rodent mutations (8 -10) is limited, but compensation and redundancy have been invoked as explanations for unexpected negative findings (11). Ultimately, the generation of potent and selective modulators of these peptide pathways is key to our ability to explore the biology of appetite control and to defining which of these pathways are likely to be the best targets for appetite suppressant drugs.NPY is a 36 -amino acid peptide that is probably the most studied putative neuropeptide regulator of appetite. In rodents, NPY is e...

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