New therapeutic opportunities for 5-HT2C receptor ligands in neuropsychiatric disorders.

Giuseppe Di Giovanni, Philippe De Deurwaerdère
Pharmacology & Therapeutics. 2016-01-01; 157: 125-162
DOI: 10.1016/j.pharmthera.2015.11.009

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The 5-HT2C receptor (R) displays a widespread distribution in the CNS and is involved in the action of 5-HT in all brain areas. Knowledge of its functional role in the CNS pathophysiology has been impaired for many years due to the lack of drugs capable of discriminating among 5-HT2R subtypes, and to a lesser extent to the 5-HT1B, 5-HT5, 5-HT6 and 5-HT7Rs. The situation has changed since the mid-90s due to the increased availability of new and selective synthesized compounds, the creation of 5-HT2C knock out mice, and the progress made in molecular biology. Many pharmacological classes of drugs including antipsychotics, antidepressants and anxiolytics display affinities toward 5-HT2CRs and new 5-HT2C ligands have been developed for various neuropsychiatric disorders. The 5-HT2CR is presumed to mediate tonic/constitutive and phasic
controls on the activity of different central neurobiological networks. Preclinical data illustrate this complexity to a point that pharmaceutical
companies developed either agonists or antagonists for the same disease. In order to better comprehend this complexity, this review will briefly describe the molecular pharmacology of 5-HT2CRs, as well as their cellular impacts in general, before addressing its central distribution in the mammalian brain. Thereafter, we review the preclinical efficacy of 5-HT2C ligands in numerous behavioral tests modeling human diseases, highlighting the multiple and competing actions of the 5-HT2CRs in neurobiological networks and monoaminergic systems. Notably, we will
focus this evidence in the context of the physiopathology of psychiatric and neurological disorders including Parkinson’s disease, levodopa-induced dyskinesia, and epilepsy.

Copyright © 2015 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.pharmthera.2015.11.009
PMID: 26617215 [Indexed for MEDLINE]

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