Serotonin (5-HT) 5-HT2C receptor (5-HT2CR) is recognized as a critical mediator of diseaserelated
pathways and behaviors based upon actions in the central nervous system (CNS). Since 5-HT2CR
is a class A G protein-coupled receptor (GPCR), drug discovery efforts have traditionally pursued the
activation of the receptor through synthetic ligands with agonists proposed for the treatment of obesity,
substance use disorders and impulse control disorders while antagonists may add value for the treatment
of anxiety, depression and schizophrenia. The most significant agonist discovery to date is the FDAapproved
anti-obesity medication lorcaserin. In recent years, efforts towards developing other mechanisms
to enhance receptor function have resulted in the discovery of Positive Allosteric Modulators
(PAMs) for the 5-HT2CR, with several molecule series now reported. The biological significance and
context for signaling and function of the 5-HT2CR, and the current status of 5-HT2CR agonists and PAMs
are discussed in this review.
Keywords: 5-HT2C receptor, Agonists, Allosteric modulation, Positive allosteric modulators, Target selectivity, Signaling bias,
Drug discovery, Ligand development, Pharmacological probes, Central nervous system disorders, Neurotherapeutics.
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Herrick-Davis, K.F.; Dinah, T. 5-HT2C receptors in the pathophysiology of CNS disease. British Journal of Clinical Pharmacology: Blackwell Science Inc, 2011, 72, 129-155.
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