1804 Table III Some Examples of Pharmacological Targets Within the CNS Assumed (predominant-) target Dopamine/norepinephrine/serotonina Mechanism of action Inhibition of uptake Stimulation of release Stimulation of GABA activityb Agonist Agonist Agonist Antagonist Antagonist Antagonist Inhibition Inhibition GABA Serotonin-receptor (5-HT2c) Serotonin-receptor (5-HT6) MC4-receptor MCH-receptor type 1 Histamine (H3-) receptor NPY (Y5) receptor AgRP PTP1B a often affecting different neurotransmitters with different relative potency b combined with other mechanisms, partly unresolved weight loss. Phentermine is thought to stimulate the release of norepinephrine and dopamine (30). As will be discussed later, the compound is now under investigation as part of a combination preparation (QnexaR) together with topiramate. Subitramine (Fig. 6) is one of the two currently approved Fig. 6 Chemical structures of some compounds predominantly acting by increasing local concen- trations of dopamine, norepi- nephrine and 5-HT in the brain: fenfluramine (banned in 1997), phentermine, and sibutramine (recently withdrawn in Europe). Witkamp Example(s)of compounds (late-stage development or approved) Subitramine Bupropion Tesofensine Phentermine Topiramate (in combinations)b Zonisamide (in combinations)b Lorcaserin Several compounds in early clinical phase Preclinical/early clinical NGD-4715 Preclinical and early clinical phase Velneperit TTP435 Trodusquemine weight-loss drugs in the US. Since early 2010, it is no longer on the market in Europe. The compound acts centrally as an uptake inhibitor of norepinephrine, seroto- nin and dopamine. The demethylated metabolites are more active than the parent compound. Subitramine is consid- ered an effective weight-loss drug, showing body-weight reductions between 5 and 10% in most trials (30). Side effects include constipation and increased blood pressure and heart rate. Bupropion (Fig. 7) is a dopamine and norepinephrine reuptake inhibitor and has also antagonist activity for Fig. 7 Chemical structures of bupropion (a dopamine and norepineph- rine reuptake inhibitor with antagonist activity for nicotine receptors) and tesofensine (a dopamine, norepinephrine and serotonin reuptake inhibitor in development).