Targeting 5-HT receptors for the treatment of obesity

Serotonin is known to have anorectic properties through centrally acting mechanisms. Three serotonin receptors have been implicated in mediating these effects: 5-HT1B, 5-HT2C and 5-HT6. Hypophagic effects are elicited through agonism of the former two receptors, whereas antagonism of the 5-HT6 receptor appears to have an anorectic effect. All three targets have been validated through extensive studies including knockout mice and selective ligand assessment. 5-HT1B receptor agonists have limited utility due to mechanism-based side effects, whereas 5-HT2C receptor agonists suffer from challenges associated with selectivity over the closely related 5-HT2A and 5-HT2B receptors. 5-HT6 receptor antagonists appear to offer great promise, although the mechanisms through which they reduce food intake and body weight are not fully understood.

Research highlights
► Approaches towards managing weight gain through serotonin receptors are discussed.
► 5-HT1B, 5-HT2C and 5-HT6 receptors have been implicated in controlling food intake.
► 5-HT1B and 5-HT2C receptor agonists face challenges around benefit to risk ratio.
► 5-HT6 receptor antagonists offer great promise in controlling weight gain.