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...

GPR120 agonists have therapeutic potential for the treatment of diabetes, but few selective agonists have been reported. We identified an indazole-6-phenylcyclopropylcarboxylic acid series of GPR120 agonists and conducted SAR studies to optimize GPR120 potency. Furthermore, we identified a (S,S)-cyclopropylcarboxylic acid structural motif which gave selectivity against GPR40. Good oral exposure was obtained with some compounds displaying unexpected high CNS penetration. Increased MDCK efflux was utilized to identify compounds such as 33 with lower CNS penetration, and activity in oral glucose tolerance studies was demonstrated. Differential activity was observed in GPR120 null and wild-type mice indicating that this effect operates through a mechanism involving GPR120 agonism.

A cyclic peptide IDOL homodimerization inhibitor identified from a genetically encoded SICLOPPS library is active in vitro and in cells.

Prolactin-releasing peptide (PrRP) and its G-proteincoupled receptor, GPR10, have been implicated in the central control of appetite and blood pressure. To determine whether mutations in these genes might contribute to morbid obesity, we screened both genes in 94 subjects with severe early-onset obesity. Four rare silent variants in PrRP and eight polymorphisms in GPR10 were found, two of which (V283I and P305L) altered amino acid sequence but were also found in U.K. Caucasian control subjects. Cells expressing the P305L variant receptor generated less intracellular calcium in response to PrRP than cells expressing the wild-type receptor. To examine whether genetic variation of the GPR10 locus might be associated with phenotypes relevant to obesity and/or blood pressure, the most common noncoding (G-62A) and coding (C914T [P305L]) polymorphisms were typed in 1,084 U.K. Caucasians. While no association was found with BMI, carriers of the P305L allelic variant had significantly lower systolic (123.95 vs. 128.55 mmHg, P < 0.05) and diastolic (74.90 vs. 78.20 mmHg, P < 0.01) blood pressure than wild-type subjects. In conclusion, we have conducted the first genetic study of GPR10 and its ligand PrRP in relation to metabolic phenotypes and have identified an association between GPR10 polymorphisms and diastolic and systolic blood pressure. The alteration in signaling properties of the receptor produced by P305L may provide a functional basis for this association. Diabetes

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