Discovery and development of 5-HT2C receptor agonists for obesity: is there light at the end of the tunnel?

Ever since the observation of late-onset obesity during the phenotypic characterization of the 5-HT2C knock-out mouse, the serotonin 5-HT2C receptor has been a drug target for obesity. Small-molecule agonists have repeatedly been shown to reduce food intake and body weight in rodent models of obesity. To date, however, only one compound, lorcaserin, has completed Phase III trials and currently awaits an US FDA decision following a negative advisory committee meeting. Agonist selectivity versus the highly homologous 5-HT2A and 5-HT2B receptors remains a significant hurdle. Ideally, a specific 5-HT2C agonist (completely devoid of 5-HT2A and 5-HT2B. activity) would be preferred. The requirement of a basic amine coupled with larger, often aromatic, hydrophobic domains, to gain selectivity, often leads to additional challenges associated with cationic amphiphilic molecules such as hERG-channel inhibition and phospholipidosis. The success of future 5-HT2C agonists will depend on further improvements in selectivity (or attainment of complete specificity) and pharmaceutical properties to permit greater and sustained receptor stimulation, while avoiding side effects associated with the activation of other 5-HT receptors.