New Horizons for Selective 5-HT_2C Receptor Ligands in Psychiatric/Neurological Disorders

The serotonin (5-HT) 5-HT_2C receptor is a key contributor to obesity, autism, psychiatric (eg, depression, schizophrenia), and neurological diseases (eg, Parkinson's disease). The diversity and regulation of the 5-HT_2C receptor signaling pathways are complex and provocatively suggest the importance of this receptor in an array of functions and indications. Therapeutic opportunities for both agonist and antagonist compounds that engage this receptor continue to emerge.

The most advanced 5-HT_2C receptor agonist in development is lorcaserin, which has completed phase III clinical trials and has submitted an NDA for the treatment of obesity (Pauli and Abdelghany, 2010). In a 12-week obesity trial, approximately 30% of patients at 10 mg b.i.d. showed >5% weight loss with lorcaserin with minimal adverse events. Earlier in development is another 5-HT_2C receptor agonist vabicaserin for the treatment of psychiatric indications. Vabicaserin is a highly selective 5-HT_2C agonist (Dunlop et al, 2010) with a strong preclinical profile supporting multiple indications. Despite initial concerns regarding potential cardiovascular liabilities, selective 5-HT_2C agonists are proving to be devoid of these concerning side effects (Pauli and Abdelghany, 2010).

Many different genetically modified animals have been created to improve understanding of the 5-HT_2C receptor. Much of the early work focused on the 5-HT_2C receptor knockout mouse that showed a hyperphagic obesity phenotype. However, the 5-HT_2C receptor is subject to RNA editing leading to different forms of the receptor that are more (unedited) or less (fully edited) sensitive to the functional effects of 5-HT_2C agonists. Therefore, more recently, transgenic animals have been developed that lock the 5-HT_2C receptor into a fully edited (VGV) or an unedited (INI) isoform. Interestingly, animals locked into the fully edited VGV form of the receptor show failure to thrive, neonatal muscular hypotonia, decreased somatic growth, and reduced fat mass despite hyperphagia, characteristics consistent with Prader–Willi syndrome (Kawahara et al, 2008; Morabito et al, 2010). The link between Prader–Willi syndrome and the 5-HT_2C receptor has also been made through regulation of the splicing of the 5-HT_2C receptor by HBII-52, a small nucleolar RNA that affects 5-HT_2C receptor function (Kishore and Stam, 2006). Patients with Prader–Willi syndrome do not express HBII-52 that regulates alternative splicing of the 5-HT_2C receptor by binding to a silencing element in exon Vb (Kishore and Stam, 2006). Moreover, these VGV mice have reduced G-protein-coupling efficiency and agonist binding but show enhanced behavioral sensitivity and serotonergic neurotransmission due to increased cell-surface expression of the 5-HT_2C receptor (Kawahara et al, 2008; Olaghere da Silva et al, 2010). Interestingly, both the nonedited INI mice and the fully edited VGV mice show anxiety-like phenotypes with the INI mice showing a depressant-like phenotype and the VGV mice showing an antidepressant-like phenotype (Mombereau et al, 2010). Taken together, these transgenic models continue to show the complexity of the regulation of this receptor and the corresponding complexity of phenotypes.

The multitude of ways that the 5-HT_2C receptor is regulated through different signaling pathways, RNA editing, and changes in receptor expression coupled with its involvement in multiple psychiatric and neurological illness place this receptor as a critical player in the understanding of CNS disorders.