Does Central Serotonin2C Receptor still have New Therapeutic Potential? | OMICS International
Biochemistry & Physiology: Open Access
Editorial Open Access
Does Central Serotonin2C Receptor still have New Therapeutic Potential?
Giuseppe Di Giovanni*
Department of Physiology & Biochemistry, Faculty of Medicine and Surgery, University of Malta, Malta
*Corresponding Author : Prof. Giuseppe Di Giovanni
Department of Physiology and Biochemistry
University of Malta
Msida MSD 2080, Malta
Received March 23, 2012; Accepted March 25, 2012; Published March 28, 2012
Citation: Giovanni GD (2012) Does Central Serotonin2C Receptor still have New Therapeutic Potential? Biochem Physiol 1:e101. doi:10.4172/2168-9652.1000e101
Copyright: © 2012 Giovanni GD. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Visit for more related articles at Biochemistry & Physiology: Open Access
View PDF Download PDF
Serotonergic receptors; Depression; Schizophrenia; Drug of abuse; Epilepsy; selective 5-HT2C drugs
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-HT2C receptor, that has emerged as a prominent central serotonin receptor subtype [3]. Since its discovery 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.
There are also many avenues that remain unexplored, so there are undoubtedly further advances to be made. For example, we are currently carrying out some experiments on the effect of 5-HT2C ligands in different models of epilepsy both generalised and focal seizures and we have obtained very promising results. Our preliminary data show that agonists for the 5-HT2C receptors have a potent antiepileptic action. These findings are in agreement with the well known activity of 5-HT2C receptor signal in controlling cell excitability [14]. Indeed, mice knock out for this receptor have higher rate of mortality and the survived ones show an increased susceptibility to seizures [14-17]. Although the available compelling evidence for the role of 5-HT2C receptors in epileptogenesis and/or propagation, no drugs are currently under development by pharmaceutical companies. This reflects a general situation of lack of investment by the pharmaceutical industry in research for CNS diseases, especially for epilepsy. Even in high income countries, epilepsy has suffered historical neglect and despite high costs and severe disabling effects, epilepsy may attract somewhat less research funding from public and private sources than other less common chronic neurological disorders. To bring to the market new drugs, the relation between the epilepsy community and pharmaceutical companies must change. Indeed, governments should understand that basic and clinical academic epilepsy research particularly needs independent support to overcome the natural tendency of the drug industry to prefer markets with a larger monetary value. Therefore, increasing funding for public laboratories is of paramount importance.
Nevertheless, I am hopeful that in the next few years, we certainly will see new compounds selective for 5-HT2C receptors, making further significant impacts on the treatment of the major neuropsychiatric disturbances, including epilepsy. In conclusion, it is apparent that 5-HT2C receptors still offer therapeutic potential, even those not yet discovered.
Di Giovanni G, Esposito E, Di Matteo V (2010) Role of serotonin in central dopamine dysfunction. CNS Neurosci Ther 16: 179-194.
Hoyer D, Clarke DE, Fozard JR, Hartig PR, Martin GR, et al. (1994) International Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). Pharmacol Rev 46: 157-203.
Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E (2006) Central serotonin2C receptor: from physiology to pathology. Curr Top Med Chem 6: 1909-1925.
Hoyer D, Pazos A, Probst A, Palacios JM (1986) Serotonin receptors in the human brain II characterization and autoradiographic localization of 5-HT1C and 5-HT2 recognition sites. Brain Res 376: 97-107.
Wacker DA, Miller KJ (2008) Agonists of the serotonin 5-HT2C receptor: preclinical and clinical progression in multiple diseases. Curr Opin Drug Discov Devel 11: 438-445.
Monck NJ, Kennett GA (2008) 5-HT2C ligands: recent progress. Prog Med Chem 46: 281-390.
Rosenzweig-Lipson S, Dunlop J, Marquis KL (2007) 5-HT2C receptor agonists as an innovative approach for psychiatric disorders. Drug News Perspect 20: 565-571.
Kostrzewa RM, Huang NY, Kostrzewa JP, Nowak P, Brus R (2007) Modeling tardive dyskinesia: predictive 5-HT2C receptor antagonist treatment. Neurotox Res 11: 41-50.
Di Giovanni G, Di Matteo V, Pierucci M, Benigno A, Esposito E (2006) Serotonin involvement in the basal ganglia pathophysiology: could the 5-HT2C receptor be a new target for therapeutic strategies? Curr Med Chem 13: 3069-3081.
Bubar MJ, Cunningham KA (2006) Serotonin 5-HT2A and 5-HT2C receptors as potential targets for modulation of psychostimulant use and dependence. Curr Top Med Chem 6: 1971-1985.
Fitzgerald LW, Burn TC, Brown BS, Patterson JP, Corjay MH, et al. (2000) Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol 57: 75-81.
Millan MJ, Marin P, Kamal M, Jockers R, Chanrion B, et al. (2011) The melatonergic agonist and clinically active antidepressant agomelatine is a neutral antagonist at 5-HT(2C) receptors. Int J Neuropsychopharmacol 14: 768-783.
Fidler MC, Sanchez M, Raether B, Weissman NJ, Smith SR, et al. (2011) A one-year randomized trial of lorcaserin for weight loss in obese and overweight adults: the BLOSSOM trial. J Clin Endocrinol Metab 96: 3067-3077.
Tecott LH, Sun LM, Akana SF, Strack AM, Lowenstein DH, et al. (2007) Eating disorder and epilepsy in mice lacking 5-HT2c serotonin receptors. Nature 374: 542-546.
Heisler LK, Chu HM, Tecott LH (1998) Epilepsy and obesity in serotonin 5-HT2C receptor mutant mice. Ann N Y Acad Sci 861: 74-78.
Applegate CD, Tecott LH (1998) Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis. Exp Neurol 154: 522-530.
Brennan TJ, Seeley WW, Kilgard M, Schreiner CE, Tecott LH (1997) Sound-induced seizures in serotonin 5-HT2c receptor mutant mice. Nat Genet 16: 387-390.
Applied Biochemistry
Biomolecular Structure and Function
Carbohydrate Biochemistry
Cell Biology Junctions
Cell Biology Techniques
Cell Death: Apoptosis
Cell Regeneration
Cell synthesis
Cellular Biochemistry
Cellular DNA Studies
Cellular Dynamics
Cellular Signalling
Cellular and Molecular Biology
Clinical_Biochemistry
Comparative Biochemistry
Environmental Biochemistry
Forensic Biochemistry
Gene Expression and Regulation
Lipid Biochemistry
Medical_Biochemistry
Methods and Techniques in Molecular Biology
Molecular Biochemistry
Molecular Biotechnology
Molecular Cell
Pesticide Biochemistry
Process Biochemistry
Protein_Biochemistry
Soil_Biochemistry
Cellular Biology Journal
Bioinformatics Journal
Transcriptomics Journal
Proteomics Journal
Physiobiochemical Metabolism Journal
Metabolomics Journal
Biochemical Technology Journal
Bioprocessing Journal
Plant Physiology Journal
Clinical Biochemistry Journal
Molecular Biology Journal
Neurophysiology Journal
Anatomy Journal
Analytical Biochemistry Journal
Pharmacology Journal
Share/Blog this article
Total views: 12236
[From(publication date):
May-2012 - Jan 29, 2022]
HTML page views : 8209
PDF downloads : 4027
add_chatinline();