The neurotransmitter serotonin (5-hydroxytryptamine; 5-HT) has a well-established role in energy homeostasis. The clinical potential of beneficially manipulating the 5-HT system is best illustrated by the efficacy of compounds such as fenfluramine and sibutramine, both of which increase 5-HT bioavailability, in the pharmacological treatment of obesity. The success of these compounds in reducing food intake and body weight has stimulated interest in dissecting the mechanisms whereby 5-HT influences energy balance. Early pharmacological studies implicated the 5-HT2C receptor (5-HT2CR; previously classified as the 5-HT1C receptor) in these effects, a suggestion supported by the later observation that genetic inactivation of the 5-HT2CR, but not other 5-HT receptors, produces hyperphagia and obesity in the mouse (Tecott et al, 1995). 5-HT2CR knockout mice also display blunted responses to fenfluramine, indicating that action at these receptors is required for the anorectic effect of this compound (Vickers et al, 1999). Collectively, these findings motivated attempts to develop selective 5-HT2CR agonists for the treatment of obesity.

Unfortunately, the high degree of sequence homology between the 5-HT2CR and 5-HT2BR has proved a major challenge in efforts to generate a truly specific high affinity 5-HT2CR agonist that does not stimulate 5-HT2BRs. Activity at the 5-HT2BR is a particular concern because action at these receptors is thought to contribute to the valvular heart disease reported in some patients following fenfluramine-phentermine use (Fitzgerald et al, 2000). Nevertheless, recent studies using combined pharmacological and genetic approaches in murine models have recently rekindled pharmaceutical interest in drug discovery programs focusing on generating more selective high affinity 5-HT2CR agonists; for example, it has been shown that fenfluramine influences appetite through the melanocortin system (Heisler et al, 2002). This brain pathway, specifically acting through the melanocortin 4 receptor, is critical for the normal regulation of energy balance, and integrates inputs from many other neuropeptides and neurotransmitters.

More recently, a distinct role for the 5-HT2CRs in glucose homeostasis has also been reported in rodents. Specifically, both a classic 5-HT2CR agonist (with binding affinity for other 5-HT receptors) and a more selective and high affinity 5-HT2CR agonist were demonstrated to reduce elevated insulin levels and improve glucose tolerance and insulin sensitivity in both genetically obese mice and in mice with diet-induced obesity, both with impaired glucose tolerance and insulin resistance (Zhou et al, 2007). Importantly, these effects were achieved at concentrations of the compounds which were too low to influence food intake, energy expenditure, locomotor activity, or body weight. These findings indicate that the 5-HT2CR may be a mechanistically novel target for the treatment of type 2 diabetes. This has been corroborated by genetic inactivation of the 5-HT2CR in mice, which, either alone or in combination with leptin deficiency, impairs glucose homeostasis (Wade et al, 2008). These findings identify a specific 5-HT receptor of relevance to a prevalent metabolic disease.

Together, these data indicate that the 5-HT2CR is an attractive and tractable potential drug target for the treatment of obesity and/or type 2 diabetes. Recent pharmaceutical efforts have led to the development of at least one compound that is currently in clinical trials for obesity treatment. Results from these trials are awaited with considerable interest.