Does Central Serotonin2C Receptor still have New Therapeutic Potential?

Abstract

Since the 1950s, when serotonin (5-HT) was discovered in the mammalian central nervous system (CNS), an enormous amount of experimental evidence has revealed the pivotal role of this biogenic amine in a number of cognitive and behavioural functions [1]. Although 5-HT is synthesized by a small group of neurons within the raphe nuclei of the brain stem, almost all parts of the CNS receive serotonergic projections. Furthermore, the importance of 5-HT modulation and the fine-tuning of its action are underlined by the large number of 5-HT binding sites found in the CNS. Hitherto, up to 15 different 5-HT receptors subtypes have been identified [2]. Large amounts of experimental evidence have explored the pathophysiological role of one of these receptors, the 5-HT 2C receptor, that has emerged as a prominent central serotonin receptor subtype [3]. Indeed, since its discovery about 25 years ago by Palacios, Pazos and Hoyer, who named it 5-HT1C [4] (see the book 5-HT2C Receptors in the Pathophysiology of CNS disease, 2011); it has been shown to play a major role in the regulation of a plethora of behaviours. Therefore, it is not surprising that experimental and clinical observations have highlighted it as a possible therapeutic target for the development of drugs for a range of CNS disorders such as schizophrenia, depression, drug abuse, eating disorders, Parkinson’s disease and epilepsy, to cite but a few [5-10]. Thus, the 5-HT2C antagonism appears to be an important feature of antipsychotic and antidepressants drugs with broad pharmacological profiles, properties that probably contribute to the treatment of negative and depressive symptoms respectively, or to the mitigation of side-effects. Although several selective agents for this receptor have been discovered, none have reached the market for the treatment of CNS disorders to date, essentially as a result of their limited efficacy and related side effects. Indeed, most of the 5-HT2C ligands have binding affinity for the 5-HT2B receptors, which may limit its therapeutic potential given that action at peripheral 5-HT2B receptors is thought to underlie the cardiopulmonary complications associated with some serotonergic drugs [11]. Several pharmaceutical companies are still very active in 5-HT2C receptors research. Nevertheless, the only compound with 5-HT2C affinity that has reached the market is agomelatine, released by Servier for the treatment of major depressive disorder with a reduced level of sexual side effects compared to some other antidepressants. Agomelatine is a melatonergic agonist (MT1 and MT2 receptors) and 5-HT2C antagonist [12]. Probably the next 5-HT2C compound to obtain the Food and Drug Administration (FDA) approval in the United States will be lorcaserin by Arena Pharmaceuticals, for the treatment of obesity [13]. Lorcaserin shows 100 times higher affinity for 5-HT2C versus other receptors, the only drawback is the exposure-response relationship for lorcaserin-emergent mammary adenocarcinoma. However, given the results of the Pathology Working Group, this may no longer be of concern since there is no statistically significant increase in mammary risk for lorcaserin patients. Therefore there is good chance for lorcaserin to gain the FDA approval later on during this year.