1808 Fig. 11 Structures of the selective H3-receptor antagonist, A-331440 and of betahistine. central H1 and H3 receptors. However, consistent evidence for efficacy in humans appears to be lacking(131). NPY Antagonists Neuropeptide Y (NPY) is a centrally acting orexigenic peptide that belongs to the same (pancreatic polypeptide-) family as PYY and PP. Signaling at neuronal Y1 and Y5 receptors produces the orexigenic effects of NPY, whereas Y2- and Y4-receptor signaling produces an anorexic phenotype due to pre-synaptic inhibition of NPY release. The latter two receptors are also the targets of the gut hormones PYY, PP and their mimetics that have been discussed in a previous section. Exploring the potential utility of the Y1 and Y5 receptors as targets, several small- molecule antagonists have been synthesized, for example by the Merck laboratories (124). An orally active Y5-receptor antagonist from Merck (MK-0557) was as unable to induce clinically meaningful weight loss in a one-year clinical trial (111). However, the Y5-receptor antagonist velneperit (S- 2367, Fig. 12) from Shionogi (http://www.shionogi.co.jp) is still in development. In a phase II trial, it showed modest but significant effects (111). Agouti-Related Protein (AgRP)- Inhibitors Similar to NPY, AgRP is an endogenous orexigenic protein acting in the basal hypothalamus. Consequently, selective Fig. 12 Chemical structure of velneperit, a Y5-receptor antagonist. Witkamp inhibitors might also have potential in inhibiting food intake. However, there do not seem to be many candidates in advanced stages of development. An exception is TTP435 from Transtech Pharma (http://www.ttpharma. com), which is reported to be a selective inhibitor of AgRP with oral activity and high brain penetration. Following successful animal studies, the compound is currently in phase II clinical trials. Other CNS Compounds and Targets A possible future target for weight management could become the bombesin receptor subtype 3 (BRS-3). This is a GPCR which is widely distributed in the brain but whose natural ligand is still unknown. Recently, a group of scientists from Merck reported the synthesis of a BRS-3 agonist that reduced food intake and increased metabolic rate in mice (132). Inhibitors of Protein Tyrosine Phosphatase (PTP1B) This enzyme is widely expressed throughout the body. In the brain, it negatively regulates leptin signaling and appears to be involved in the development of leptin resistance (133). As leptin resistance plays a role in obesity, inhibition of central PTP1B activity may provide a way to overcome this. In addition, peripheral PTP1B inhibition might improve insulin sensitivity in muscle and liver. Recently, Banno et al. (133) showed that PTP1B plays an important role in POMC neurons in the hypothalamus. The natural compound trodusquemine (Fig. 13) is a central and peripheral inhibitor of PTP1B. It showed weight loss and beneficial effects on fasting blood glucose, blood cholesterol and triglyceride levels in obese animals (134–136). The compound has been in development as MSI-1436 by Genaera, who ended phase I clinical studies in 2007. Since this company has ended its business, its current status and perspective are unclear, although the compound is used as experimental tool. COMPOUNDS AIMING TO REDUCE FAT MASS In addition to reducing energy intake, different pharmaco- logical approaches are being evaluated to reach weight reduction or improve health by increasing energy expendi- ture or by reducing or redistributing adipose tissue. The latter may be useful to change “risky” (visceral) fat into less risk-bearing fat depots. In the food supplement area, there are many preparations claiming to help “burn” fat. Although some compounds, including caffeine, ephedrine and epigallocatechin gallate (EGCG), have been shown to possess some activity, sustained effects are generally