Current and Future Drug Targets in Weight Management nicotine receptors (30,110,111). It was originally developed as an antidepressant and for smoking cessation, for which it is approved in the US, but later showed utility in the treatment of obesity (110,111). Studies have shown that the compound can cause effective, long-term (1-year) weight loss when combined with lifestyle modification, and it appears to be more effective in patients not suffering from depression (111). It is also suggested that bupropion could serve as a valuable adjunct therapy to elevate mood in depressed patients in whom weight gain, secondary to antidepressant therapy, is an issue (111). Bupropion is currently also under clinical investigation in two different combinations, one together with the anti-epileptic drug zonisamide (Empatic®) and the other with the opioid antagonist naltrexone (Contrave®). These will be discussed in a next section. Tesofensine (Fig. 7) is a dopamine, norepinephrine and serotonin reuptake inhibitor developed by the Danish company Neurosearch. The compound has successfully passed phase II clinical testing (ClinicalTrial.gov NCT00394667), in which it showed dose-dependent weight loss (112), and has just entered phase III testing (30). Combination Therapies Based on Existing Drugs Interestingly, two older compounds of the previously described class of compound modulating levels of mono- amines, phentermine and bupropion, are currently under- going their renaissance in combination preparations with other existing drugs. Two of these combinations, Contrave® (bupropion plus naltrexone) and Qnexa® (phentermine plus topiramate) have already passed phase III testing. With the third combination, Empatic® (bupropion plus zonisa- mide), phase III testing will probably start shortly. The matching compounds in these combinations were initially developed as anti-epileptic drugs (zonisamide and top- iramate) or as opioid antagonist (naltrexone). Topiramate and zonisamine are known to interact with different pathways, including GABA-ergic transmission. However, whilst GABA plays an important role in the brain, GABA- related targets do not appear to have provided practical strategies for weight management so far. The same holds true for opioids. Although there is considerable evidence that μ-, κ- and δ-opioid receptors located in the reward- related brain areas are involved in control of food intake, this has not resulted in new molecules for weight management (30). One of the explanations might be that opioid antagonists as monotherapy have a rather complex effect on eating behavior, mainly affecting hedonic components and not satiety or satiation (30). Furthermore, the opioid system has many connections and functions within the CNS, which also increase the risk for side effects when single compounds would be used at pharmacolog- ically active doses. 1805 Phentermine Plus Topiramate (Qnexa®) The amphetamine derivative phentermine (Fig. 6) is currently approved in the US as a short-term treatment for weight loss (recommended dose 37.5 mg/day), whereas topiramate (Fig. 8) is indicated for treatment of seizures (recommended dose 400 mg/day) or prevention of mi- graine headaches (recommended dose 100 mg/day). The use of topiramate for weight management is a typical example of serendipity in the discovery of drugs in this area. It was not only discovered incidentally as anti-convulsant, but was also shown to possess anti-craving and weight loss effects (108). The mechanism(s) by which topiramate induces weight loss effects are still largely unknown. The combination, given in a slow-release formulation intended for once-daily administration allows lower doses of the individual compounds and is reported to cause fewer side effects than the individual compounds. Results from the recent EQUIP phase III trial sponsored by Vivus Inc. (Clintrial.gov NCT00554216), in which 1267 persons with a mean BMI of 42 kg/m2 were enrolled for 56 weeks, indicate that the combination of 15 mg phentermine with 92 mg topiramate resulted in a mean weight loss of 14.4%, whereas persons in the placebo group lost 2.2% (113). Results were also in agreement with the FDA efficacy benchmarks in terms of % of persons showing more than 5, 10 or 15% weight loss. This was associated with significantly different (from placebo) reduction in waist circumference and systolic and diastolic blood pressure. In another phase III study (QONQUER), the combination Fig. 8 Structures of topiramate and zonisamide, originally developed as anti-epileptic compounds. Currently under development in combination preparations.