Abstract: 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 theGPCR 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.
Otras publicaciones de la misma revista o congreso con autores/as de la Universidad de Cantabria