Current and Future Drug Targets in Weight Management years (121). However, in September–October 2010, the FDA rejected the application because of safety issues that had been found in the preclinical data files. The applicants expressed their confidence in being able to alleviate these concerns, but at this stage it is unclear what the con- sequences for the further development of lorcaserin are. 5-HT6 Agonists Another serotonin-associated target that is increasingly receiving attention is the 5-HT6 receptor (see (116, 119) for reviews). The 5-HT6 receptor is almost exclusively distributed within the central nervous system, which is rather unusual for a member of the serotonin receptor family. This is considered an advantage, as this facilitates selective modulation. The 5-HT6 receptor has also become an attractive target for potential new antipsychotics and antidepressants. Many new 5-HT6 ligands have been synthesized with different structures (119). Among these, a number of compounds have shown effects on food intake or body weight in rodents, and some have entered clinical testing. The next few years will be decisive in demonstrating the potential of this target. Dopaminergic Ligands Compared to 5-HT receptors and despite the role of dopamine in regulating eating behavior, dopamine receptors do not appear to be considered as attractive targets at the moment. Preclinical studies suggest that D3 antagonists can be effective in reducing food intake (122). GlaxoSmithKline is currently investigating the D3 antagonist GSK598809 for use with compulsive overeating (ClinicalTrials.gov NCT01039454). MC4R (Melanocortin 4 Receptor) Agonists and MCH-R1 (Melanin-Concentrating Hormone Receptor 1) Antagonists The melanocortin system plays an important role in the central regulation of energy balance (123). The POMC (pro-opiomelanocortin) gene encodes several anorexigenic peptides that can activate at least five melanocortin receptor subtypes. These peptides include α-,β-,γ-melano- cyte-stimulating hormone (α-MSH, β-MSH and γ-MSH) and adrenocorticotropin (ACTH). Of the different recep- tors, the melanocortin 4 receptor (MC4R) is receiving considerable interest as a potential target. Several small- molecule agonists have been synthesized. See for structures for example (124) and for a very extensive list also (125). The clinical usefulness of this group remains to be established. Results with the MC4R agonist MK-0493 from MSD in humans were disappointing (126). 1807 Melanin-concentrating hormone (MCH) is an endoge- nous small cyclic peptide that increases food intake via interaction with the MCH-R1 receptor. MCH-R1 antago- nists have been shown to inhibit food-intake in rodents, and several of such compounds have been synthesized (125,127). Remarkably, cardiovascular side effects involving hERG binding and the potential for subsequent drug- induced QT prolongation have presented major hurdles in a significant number of MCH-R1 research programs (127). Nevertheless, some molecules, including NGD-4715 (Fig. 10), have reached phase II. Another example is BMS- 830216 (Bristol-Myers Squibb), which is also entering phase II (ClinicalTrials.gov NCT00909766). H3 Receptor Antagonists Central histamine signaling has been implicated in appetite regulation, and inhibition of H1 receptor signaling or stimulation of H3 receptors may also play a role in the weight gain associated with antipsychotic medication. Histamine signaling is auto-regulated by the presynaptic H3-histamine receptor, which inhibits histamine synthesis and release when activated (128–130). Both H1-receptor agonists and H3-receptor antagonists have been investigat- ed as anti-obesity therapeutics. However, most attention has focused on the development of antagonists for the H3- receptor, since these are expressed almost exclusively in the central nervous system. Several compounds have been synthesized; examples are given in (128) and (129). In preclinical testing, the selective H3-receptor antagonist, A- 331440 (Fig. 11), at oral dosages of 5 mg/kg and 15 mg/kg twice daily, induced significant weight loss in mice (111). Another example is HPP404 from Transtech Pharma (http://www.ttpharma.com), which is also reported to be in phase I. Many other H3 antagonists are in clinical development for indications different from obesity (128,129). The H3 antagonist SCH-497079, which was acquired by Merck&Co, has undergone phase II testing for weight management, but its status is presently unknown. The compound betahistine (Histalean®, Fig. 11), which is on the market in Canada and Europe for vertigo, has also been claimed to decrease food intake via blockade of Fig. 10 Structure of NGD-4715, a MCH-R1 antagonist presently in phase II.