5-HT2C receptor agonists as potential drugs for the treatment of obesity

An association between the brain serotonin (5-HT) system and feeding has been postulated since the 1970's but it has only been in recent years that the nature of 5-HT-mediated hypophagia has become well understood, and the receptor subtypes responsible for the effect better defined. The invention and utilisation of subtype-selective 5-HT receptor antagonists has demonstrated that the 5-HT(2C) receptor is of paramount importance in this regard. Importantly, ethological studies of animal behaviour have shown that the hypophagia resulting from 5-HT(2C) receptor activation is likely to be a consequence of increased satiety and this is in contrast to hypophagia following 5-HT(2A) receptor activation. Furthermore, recent studies have also shown that 5-HT(2C) receptor agonists not only reduce feeding when acutely administered to rats or mice, they can also reduce body weight without inducing tolerance when administered chronically to obese animals. These observations have led researchers to conclude that selective 5-HT(2C) receptor agonists have the potential to be effective anti-obesity agents. Encouragingly, this suggestion is supported by both direct and indirect evidence from clinical studies. Indirect evidence stems from recent observations that the clinically effective anorectic agent d-fenfluramine exerts its hypophagic and weight-loss effects via 5-HT(2C) receptor activation. More direct clinical evidence derives from the use of the prototypical 5-HT(2C) receptor agonist m-chlorophenylpiperazine (mCPP), with which both acute hypophagia and body-weight loss have been observed. The current paper therefore reviews both the pre-clinical and clinical evidence supporting the use of 5-HT(2C) receptor agonists for the treatment of obesity and assesses the developments that have been made in this regard to date.