Discovery and development of 5-HT(₂C) receptor agonists for obesity: is there light at the end of the tunnel?

Future Med Chem. 2010 Dec;2(12):1761-75. doi: 10.4155/fmc.10.261.


Ever since the observation of late-onset obesity during the phenotypic characterization of the 5-HT(₂C) knock-out mouse, the serotonin 5-HT(₂C) 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-HT(₂A) and 5-HT(₂B) receptors remains a significant hurdle. Ideally, a specific 5-HT(₂C) agonist (completely devoid of 5-HT(₂A) and 5-HT(₂B) 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-HT(₂C) 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.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacology
  • Anti-Obesity Agents / therapeutic use*
  • Benzazepines / chemistry
  • Benzazepines / pharmacology
  • Benzazepines / therapeutic use*
  • Body Weight / drug effects
  • Drug Discovery / trends
  • Eating / drug effects
  • Humans
  • Molecular Sequence Data
  • Obesity / drug therapy*
  • Obesity / metabolism
  • Receptor, Serotonin, 5-HT2C / metabolism*
  • Serotonin 5-HT2 Receptor Agonists / chemistry*
  • Serotonin 5-HT2 Receptor Agonists / pharmacology
  • Serotonin 5-HT2 Receptor Agonists / therapeutic use*


  • Anti-Obesity Agents
  • Benzazepines
  • Receptor, Serotonin, 5-HT2C
  • Serotonin 5-HT2 Receptor Agonists
  • lorcaserin