1800 pleiotropic regulator of energy uptake and storage and of non- homeostatic eating behavior (76,77). In the past, these mechanisms were beneficial in order to survive periods of food shortage. The first generation CB1 blockers, including rimonabant, were reverse agonists developed to act on receptors present within the CNS. Later, it became clear that CB1 receptors were also present outside the CNS. Further- more, it is now assumed that the central effects of rimonabant are responsible for the short-term reduction of food-intake, whereas the more sustained effects on body weight and the improvement of insulin resistance and blood lipids are more due to its peripheral actions. The failure of rimonabant because of depression-related side effects in predisposed persons shocked the pharma industry. By the end of 2008, at least nine companies terminated active development projects with CB1 blockers, including some with compounds in a well- advanced stage of development such as taranabant (Merck) and CP-945,598 (otanabant, Pfizer). However, interest in CB1 modulation in relation to metabolic diseases has not complete- ly disappeared (76,78), and, in principle, a number of therapeutic options have remained. These include the use of CB1 neutral antagonists or partial agonists as opposed to reverse agonists, such as rimonabant, or by using so-called peripherally restricted CB1 antagonists (78–83). Several peripherally restricted CB1 blockers have been synthesized and characterized (82,84,85). These second-generation CB1 blockers are more lipophilic, leading to lower brain concen- trations. Some compounds have shown sustained effect on weight without giving the temporal suppression of food intake seen with rimonabant (82,84,85). Fig. 5 shows some examples. LH-21 (84) was one of the first compounds described in this class, and the 7-carbamoylmethyl-pyrazole- carboximide derivatives have been synthesized by Danish 7TM Pharma (85). In early 2010, 7TM Pharma announced that it had successfully completed a phase I clinical trial with the drug candidate TM38837 showing favorable pharmaco- kinetic properties in humans (86). Compounds Interfering with Signaling Pathways to the Brain As earlier described, satiety signals from the gut are transferred to the brain via neural pathways and through the circulation via peptide hormones. The latter offers options for pharmacological intervention, which in some cases has provided effective approaches. Some examples are listed in Table II. Amylin Analogues Amylin is a peptide of 37 amino acids which is co-released with insulin by the pancreas (56,87). Its primary sites of action are thought to be located in the brainstem. Amylin Witkamp Fig. 5 Chemical structure of rimonabant, the first clinically developed CB1 blocker, which failed during (US) and after (EU) registration and some examples of second-generation CB1 blockers. While LH-21 has not been developed into the clinic, compounds belonging to the 7-carbamoylmethyl- pyrazole-carboximide derivatives are still in development. analogues were originally developed for therapeutic use in diabetes but were also shown to cause weight loss, for example in obese patients with type 2 diabetes (88). The use of the endogenous peptide might increase the risk for the formation of amyloid fibrils (56). However, the analogue pramlintide (Symlin®, Pubchem CID 16132446), devel- oped by Amylin Pharmaceuticals, does not contain the sequence that is considered responsible for this effect. Pramlintide is already available in the US as an injectable antihyperglycemic drug for diabetic patients who also use insulin. An interesting preparation which is currently in development is the combination of pramlintide with metreleptin (89). Metreleptin is a synthetic analogue of