A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

Abstract

This paper is a personal account on the discovery and characterization of the 5-HT_2C receptor (first known as the 5-HT_1C receptor) over 30 years ago and how it translated into a number of unsuspected features for a G protein-coupled receptor (GPCR) and a diversity of clinical applications. The 5-HT_2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT_1CR, the 5-HT_2CR was discovered while studying the pharmacological features and the distribution of [³H]mesulergine-labelled sites, primarily in the brain using radioligand binding and slice autoradiography. Mesulergine (SDZ CU-085), was, at the time, best defined as a ligand with serotonergic and dopaminergic properties. Autoradiographic studies showed remarkably strong [³H]mesulergine-labelling to the rat choroid plexus. [³H]mesulergine-labelled sites had pharmacological properties different from, at the time, known or purported 5-HT receptors. In spite of similarities with 5-HT₂ binding, the new binding site was called 5-HT_1C because of its very high affinity for 5-HT itself. Within the following 10 years, the 5-HT_1CR (later named 5-HT_2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first 5-HT receptors to be sequenced and cloned. The 5-HT_2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT_2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT_2CR splice variants. Intense research led to therapeutically active 5-HT_2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of antidepressants and antipsychotics are 5-HT_2CR antagonists/inverse agonists. Agomelatine, a 5-HT_2CR 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 5-HT_2CR is involved in spinal cord injury-induced spasms of the lower limbs, which can be treated with 5-HT_2CR antagonists/inverse agonists such as cyproheptadine or SB206553. The 5-HT_2CR may play a role in schizophrenia and epilepsy. Vabicaserin, a 5-HT_2CR 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 5-HT_2CR ligands, as suggested by a number of preclinical and/or genome-wide association studies (GWAS) on depression, suicide, sexual dysfunction, addictions and obesity. The 5-HT_2CR is clearly affected by a number of established antidepressants/antipsychotics and may be one of the culprits in antipsychotic-induced weight gain.

Keywords: 5-HT2C receptor; Agomelatine; Anxiety; Depression; Drug addictions; GPCR; GWAS; Heteromers; Human brain; In situ hybridization; Lorcaserin; Mesulergine; Obesity; RNA editing; Receptor autoradiography; Receptor homomers; Schizophrenia; Sertindole; Smoking cessation; Species differences; Spinal cord injury; Suicide; Vabicaserin.