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Contemporary Perspective on 5-HT2C Receptor Function and its Pharmacological Targeting

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Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is an attractive target for the treatment of several chronic health disorders. Its involvement in energy balance led to launch the 5-HT2CR agonist lorcaserin as an anti-obesity medication. Agonists with selectivity at the ...

Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is an attractive target for the treatment of several chronic health disorders. Its involvement in energy balance led to launch the 5-HT2CR agonist lorcaserin as an anti-obesity medication. Agonists with selectivity at the 5-HT2CR over the homologous 5-HT2AR and 5-HT2BR have also been tested in clinical trials for the treatment of substance use disorders and schizophrenia, due in part to the intimate link between the 5-HT2CR and central dopaminergic function. The potential for 5-HT2CR agonist medications for treatment of impulsive/compulsive disorders, anxiety, depression, epilepsy or spinal cord injury also remain in the spotlight. There remains much to learn about the biology of the 5-HT2CR, the potential for 5-HT2CR ligands as disease-modifying therapeutics, as well as the nuances of drug discovery efforts to improve selectivity and targeting of small molecules for the 5-HT2CR over the 5-HT2A/2BRs which are in the same family.

Pharmacological actions at the 5-HT2CR modulate multiple functions of the central nervous system (CNS), impacting a multitude of neurobiological networks, neurotransmitter systems, and behaviors. Its impact is region-dependent in brain and spinal cord, and the 5-HT2CR exhibits phasic, tonic and even constitutive activity toward intracellular signaling pathways depending upon the conditions under study. Moreover, the 5-HT2CR couples distinct intracellular signaling pathways, raising the possibility for the discovery of novel biased ligands and inverse agonists. Finally, allosteric modulators are also an option to narrow side effect profiles associated with classical agonists.

The future for the targeted development of 5-HT2CR ligands requires intense effort to uncover key molecular, cellular and integrative mechanisms within this receptor system. The allure of uncovering the scientific secrets of the 5-HT2CR system is the prospects for therapeutics, but also the amazing 5-HT2CR regulatory features devised by biology, which include pre-transcriptional regulations, alternative splicing and post-transcriptional RNA editing. RNA editing is an important molecular process from a pharmacological perspective because of the generation of multiple 5-HT2CR isoforms with distinct pharmacological properties. Most recently, the 5-HT2CR has been shown to exist in oligomeric formations and the 5-HT2CR is thought to signal as homodimer. Heterodimers, notably with family members (5-HT2AR, 5-HT2BR) as well as other G protein-coupled receptors [e.g., ghrelin GHS receptor1╬▒] change the molecular and cellular impact of the receptor signaling. Finally, one of the most complicated issues in the field of 5-HT2CR pharmacology is to understand its integrative properties. Indeed, according to its widespread expression, the 5-HT2CR regulates multiple facets of brain function, often through the involvement of several receptors expressed in distinct brain regions, sometimes acting in an opposite functional manner. Thus, in a given neurobiological network, it is still difficult to predict the functional 5-HT2CR output based upon the utilization of pharmacological ligands, particularly in vivo.

The purpose of this collection is to provide a contemporary perspective dedicated to 5-HT2CR function and its pharmacological targeting in both clinical and preclinical investigations. The collection also welcomes articles aimed at understanding the molecular events impacting 5-HT2CR function and expression which are viewed as a required knowledge for establishing novel and more targeted pharmacological approaches.


Keywords: Neurobiology, metabolism, system interaction, behavior, molecular pharmacology


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