A short history of the 5HTSubscript2C/Subscrip

Authors: Jose M Palacios Angel Pazos Daniel Hoyer

Publish Date: 2017/03/07

Volume: 234, Issue: 9-10, Pages: 1395-1418

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Abstract

This paper is a personal account on the discovery and characterization of the 5HT2C receptor first known as the 5HT1C receptor over 30 years ago and how it translated into a number of unsuspected features for a G proteincoupled receptor GPCR and a diversity of clinical applications The 5HT2C receptor is one of the most intriguing members of the GPCR superfamily Initially referred to as 5HT1CR the 5HT2CR was discovered while studying the pharmacological features and the distribution of 3Hmesulerginelabelled sites primarily in the brain using radioligand binding and slice autoradiography Mesulergine SDZ CU085 was at the time best defined as a ligand with serotonergic and dopaminergic properties Autoradiographic studies showed remarkably strong 3Hmesulerginelabelling to the rat choroid plexus 3Hmesulerginelabelled sites had pharmacological properties different from at the time known or purported 5HT receptors In spite of similarities with 5HT2 binding the new binding site was called 5HT1C because of its very high affinity for 5HT itself Within the following 10 years the 5HT1CR later named 5HT2C was extensively characterised pharmacologically anatomically and functionally it was one of the first 5HT receptors to be sequenced and cloned The 5HT2CR is a GPCR with a very complex gene structure It constitutes a rarity in the GPCR family many 5HT2CR variants exist especially in humans due to RNA editing in addition to a few 5HT2CR splice variants Intense research led to therapeutically active 5HT2C receptor ligands both antagonists or inverse agonists and agonists keeping in mind that a number of antidepressants and antipsychotics are 5HT2CR antagonists/inverse agonists Agomelatine a 5HT2CR antagonist is registered for the treatment of major depression The agonist Lorcaserin is registered for the treatment of aspects of obesity and has further potential in addiction especially nicotine/ smoking There is good evidence that the 5HT2CR is involved in spinal cord injuryinduced spasms of the lower limbs which can be treated with 5HT2CR antagonists/inverse agonists such as cyproheptadine or SB206553 The 5HT2CR may play a role in schizophrenia and epilepsy Vabicaserin a 5HT2CR agonist has been in development for the treatment of schizophrenia and obesity but was stopped As is common there is potential for further indications for 5HT2CR ligands as suggested by a number of preclinical and/or genomewide association studies GWAS on depression suicide sexual dysfunction addictions and obesity The 5HT2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychoticinduced weight gain

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