Current and Future Drug Targets in Weight Management Blocking Ghrelin Activity In contrast to the previously described gut hormones, ghrelin stimulates eating. Ghrelin is a 28-amino-acid polypeptide released from the gastric oxyntic cells. Its plasma levels show a marked rise shortly before the start of a meal (100). The peptide increases food intake both in rodents and humans. Ghrelin has been shown to act on the growth hormone secretagogue receptor 1A (GHS-R1a), which is expressed in several brain areas (101). In order to bind, ghrelin needs to be bio-activated through acylation with a medium-chain fatty acid. The enzyme involved, gastric O-acyltransferase (GOAT), has also attracted inter- est as a potential target to modulate ghrelin activity (102). Some discussion is remaining on the potential role of non- acylated ghrelin (56). Recent studies suggest that ghrelin activates reward-seeking circuits and increases the incentive value of palatable foods in particular (101). To modulate ghrelin effects, blocking the receptor using small-molecule antagonists seems an interesting option. Indeed, several GHS-R1a blockers were synthesized and characterized (for example (103,104)). However, no molecules appear to have reached the clinical phase to date. Alternative strategies are targeting ghrelin itself by ghrelin RNA aptamers (so-called Spiegelmers, including NOX-B11) developed by Berlin- based company NOXXON Pharma AG (105) or by an anti-ghrelin vaccine (106). The aptamer strategy was licensed to Pfizer and has not yet reached clinical testing. Although ghrelin vaccination has shown promising results in animals (106), human tests have not given suitable results so far. Leptin Analogues Leptin is not a gut hormone but secreted by adipose tissue. It has been shown to act as both a short- and long-term regulator of energy balance and to signal in the arcuate nucleus, where it inhibits NPY/AgRP signaling and stimulates POMC/CART signaling. After the discovery of leptin, expectations were high regarding its potential to reduce appetite. However, early clinical trials of leptin therapy for the treatment of obesity failed because the majority of obese patients exhibit leptin resistance. Recent- ly, though, leptin has reemerged as a targeted antiobesity therapeutic in combination with the amylin analogue pramlintide (see section on amylin analogues). DRUGS ACTING ON NEUROTRANSMISSION AND RECEPTORS IN THE CNS The regulation of food intake and body weight within the central nervous system occurs at different levels with 1803 multiple systems being involved. A detailed description falls beyond the scope of this article. For recent reviews, see for example (32,55,107–109). Briefly, different stimuli, includ- ing satiety hormones, signal coming in via the N. vagus, and nutrients in plasma are sensed and integrated by the brainstem and the hypothalamus. In the arcuate nucleus of the basal hypothalamus, the orexigenic (appetite stimu- lating) neuropeptide Y (NPY) and agouti-related protein (AgRP)-expressing neurons counterbalance anorexigenic pro-opiomelanocortin (POMC) and cocaine-amphetamine- regulated transcript (CART)-expressing neurons (see also Fig. 1). 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 their presynaptic inhibition of NPY release. The latter two receptors are also the targets of the gut hormones PYY and PP that have been discussed in the previous section. The resulting level of metabolic balance in the basal hypothalamus is integrated with signals from brainstem centers and input from the lateral hypothalamus and further projected to so-called second-order hypothalamic neurons. The liking (pleasure/palatability) and wanting (appetite/incentive motivation) associated with the in- creased availability and variety of food are processed in the cortico-limbic structures, a series of synaptically interconnected circuits linking the prefrontal cortex, amyg- dala, ventral tegmental area (VTA), nucleus accumbens (NAc) and ventral pallidum with the medial forebrain bundle (MFB). Despite this complexity and apparently tightly regulated balance, there is a remarkably high research activity in the development of compounds for weight management that act within the CNS. Some of the most advanced preparations in development belong to this category. However, the contribution of old molecules, initially developed for other indications, is also considerable in this group. Remarkable is also the emergence of combination therapies in this category, aiming to modulate different targets in parallel, while reducing the dose of the individual compounds to minimize side effects. Table III briefly summarizes the main representatives and targets of this category. Note that many CNS compounds are modulating different targets or pathways in parallel. Compounds Predominantly Modulating Local Availability of Dopamine, Norepinephrine and Serotonin in the Brains This group also comprises the amphetamine-related compounds fenfluramine (Fig. 6) and dexfenfluramine, which were banned in 1997. Another amphetamine derivative, phentermine (Fig. 6), once popular in fen-phen combinations with fenfluramine and dexfenfluramine, is currently approved in the US as a short-term treatment for