This paper is a personal account on the discovery and characterization of the
5-HT2C receptor (first known as the 5-HT1C 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-HT2C receptor is one of the most intriguing members of the GPCR superfamily. Initially referred to as 5-HT1CR, the 5-HT2CR 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-HT1C because of its very high affinity for
5-HT itself. Within the following 10 years, the 5-HT1CR (later named 5-HT2C) was extensively characterised pharmacologically, anatomically and functionally: it was one of the first
5-HT receptors to be sequenced and cloned. The 5-HT2CR is a GPCR, with a very complex gene structure. It constitutes a rarity in the GPCR family: many 5-HT2CR variants exist, especially in humans, due to RNA editing, in addition to a few 5-HT2CR splice variants. Intense research led to therapeutically active
5-HT2C receptor ligands, both antagonists (or inverse agonists) and agonists: keeping in mind that a number of
antidepressants and
antipsychotics are 5-HT2CR antagonists/inverse agonists.
Agomelatine, a 5-HT2CR 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-HT2CR is involved in
spinal cord injury-induced
spasms of the lower limbs, which can be treated with 5-HT2CR antagonists/inverse agonists such as
cyproheptadine or
SB206553. The 5-HT2CR may play a role in
schizophrenia and
epilepsy.
Vabicaserin, a 5-HT2CR 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-HT2CR
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-HT2CR is clearly affected by a number of established
antidepressants/
antipsychotics and may be one of the culprits in
antipsychotic-induced
weight gain.