Abstract
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.
Financial & competing interests disclosure
The authors are employees of Bristol-Myers Squibb. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.