New and Promising Drugs for Obesity

As the obesity epidemic continues, there is demand for more potent and with less side effects anti-obesity drugs. Serotonin is widely- known to participate in the process of satiety. A novel drug that has been associated with serotonin, has been FDA approved in 2012 for the treatment of obesity and is called lorcaserin. It acts as a selective 5-HT2C agonist on pro-opiomelanocortin neurons, thus inducing alpha- melanocyte stimulating hormone (alpha-MSH) and thereby, decreasing appetite. Bupropion also stimulates pro-opiomelanocortin neurons in the hypothalamus resulting in an anorexigenic effect. The combination of phentermine and extended-release topiramate has recently gained approval for the treatment of obesity by the FDA. Phentermine stimulates the release of noradrenaline, dopamine, and serotonin, in a non-selective manner. Phentermine has already been tried as a short-term therapy for obesity, while topiramate, a drug used for the treatment of epilepsy, has been proposed as an anti-obesity drug, based on remarks of weight loss among patients treated with this anticonvulsant drug. Besides, it has been documented that “glucagon-like peptide 1” (GLP-1), and glucagon, together with oxyntomodulin (OXM) have the potential to produce brown adipose tissue (BAT) thermogenesis by means of a centrally involved sympathetic pathway. As the use of “GLP-1 receptor agonists” for treating type 2 diabetic patients has become widespread, this category of drugs could probably be efficacious in combating obesity in the near future. In fact, exanetide and liraglutide have been recently FDA approved as anti-obesity drugs. Orlistat together with cetilistat are gastrointestinal and pancreatic lipase inhibitors, which result in reduced fat absorption, but cetilistat is suggested to have better tolerability than orlistat. Recent data has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. Besides, targeting peroxisome proliferator activated-receptor gamma, seems to be a promising pathway to control the obesity epidemic in the future. Other novel drugs, which have been explored and seem promising against obesity and therefore are worth mentioning are beloranib, velerenib and tesofensine. Tesofensine possesses inhibitory properties regarding serotonin, dopamine and mainly noradrenaline. Velneperit is an oral, small-molecule NPY5 receptor antagonist, which acts centrally and is given once daily. Neuropeptide Y (NPY), an appetite-stimulating substance, has a key -role in homeostasis of energy balance, especially under food deprivation conditions. Velneperit counteracts elevated NPY levels, thus producing sustained weight loss. Beloranib, “an analog of the natural substance fumagillin, is a methionine amino peptidase 2 inhibitor (MetAP2)”. The ability of “MetAP2 to suppress extracellular regulated kinases 1 and 2 (ERK1/2)” is thought to act as the major the mechanism associated with beloranib’s potential against obesity. Brown adipose tissue possesses too many vessels. It is by means of these precursor cells that are present in vessels, that adipogenesis is controlled by angiogenesis. Adipose-derived precursor cells produce peptides, such as “vascular endothelial growth factor (VEGF)”, leptin, resistin, and visfatin, and matrix metalloproteinases (MMPs), which are implicated in and promote angiogenesis. Therefore, new targets such as VEGF, matrix- metalloproteinases and sirtuin receptors are currently being investigated, with regards to their anti-obesity potential.

Keywords: Beloranib, brown adipose tissue, bupropion, cetilistat, GLP-1 analogues, incretin effect, lorcaserin, obesity epidemic, orexins, oxyntomodulin, oxytocin, phentermine/topiramate ER, PPARγ, tesofensine, VEGF, velneperit.