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

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

Antihistaminic properties of cicletanine in human isolated coronary arteries.

Cicletanine was tested as an antagonist of the various actions of histamine in coronary artery rings isolated from old (mostly atherosclerotic) and young (non-atherosclerotic) patients. Histamine mainly induced concentration-dependent contractions in arteries from old patients. Cicletanine antagonized this effect with a pA2 value of 6.9 (slope factor of 0.94), revealing in some cases a relaxant effect of histamine. In addition, cicletanine increased the threshold concentration of histamine required to trigger spastic, indomethacin-sensitive rhythmic contractions in (some) rings of the oldest patient. At variance with what occurred in coronary rings from old patients, the predominant effect of histamine in rings from young patients was relaxation. This relaxation remained unaltered by cicletanine (1 microM). As a whole, these results extend the histamine H1 antagonistic activity of cicletanine to human coronary arteries. If histamine is involved in the promotion of vasospasm, then cicletanine could be of potential benefit to patients, without apparently affecting the relaxant response to histamine in non-cardiac patients

Spontaneous rhythmic contractions of human saphenous veins isolated from old subjects are sensitive to cyclooxygenase inhibitors

Spontaneous rhythmic contractions were observed in some preparations of human isolated saphenous veins from old (greater than 60 years) subjects. These contractions were insensitive to adrenergic and histaminergic blockers, but were abolished by the cyclooxygenase inhibitors, aspirin and indomethacin, indicating the participation of endogenous eicosanoids

Modulatory role of the vascular endothelium in the contractility of human isolated internal mammary artery.

1. Endothelium-dependent relaxant responses and modulation of contractile responses were investigated in human isolated internal mammary artery (HIMA), a vessel widely used for coronary bypass surgery. 2. Acetylcholine and ionophore A23187 (both 10 nM-1 microM) elicited concentration-dependent relaxations of precontracted HIMA. These relaxations were abolished after rubbing of the endothelium, they were inhibited by methylene blue and were insensitive to indomethacin. 3. Histamine at concentrations lower than 10 microM elicited an endothelium-dependent, methylene blue-sensitive relaxation of precontracted HIMA. This effect of histamine was inhibited by the H1-receptor antagonist mepyramine. Bradykinin, noradrenaline and alpha 2-adrenoceptor agonists (in the presence of prazosin) did not relax unrubbed HIMA in which acetylcholine or A23187 were shown to be efficient. 4. Tissue levels of guanosine-3':5'-monophosphate (cyclic GMP) were found to be significantly higher in unrubbed HIMA rings than in matched rubbed rings. 5. Methylene blue evoked a slow contraction in resting HIMA, and this contraction was significantly greater in unrubbed than in rubbed preparations. Also, methylene blue enhanced the contractile response of HIMA to noradrenaline and this potentiating effect was significantly greater in unrubbed than in rubbed preparations. Indomethacin induced a slow contraction, of similar magnitude in unrubbed and rubbed HIMA rings. 6. In resting HIMA, the concentration-effect curve of noradrenaline-induced contraction was significantly shifted to the left after rubbing of the endothelium, without change in the maximal responses. In unrubbed rings the EC50 value of noradrenaline was about 2 fold that in rubbed rings. 7. Histamine also contracted resting HIMA in a concentration-dependent manner and in addition, it triggered rhythmic activity. This rhythmic activity was more prominent in unrubbed preparations and could be partially inhibited by indomethacin. The concentration-effect curve of histamine-induced contractions was displaced to the left after rubbing the endothelium, without changes in the maximal responses. The EC50 value of histamine in unrubbed rings was 4 to 9 fold that found in rubbed rings, depending on the level of tension taken into account for the concentration-effect curve during rhythmic contractions. 8. In the presence of nifedipine (3 microM), noradrenaline-induced contractions were not significantly altered, whereas histamine-induced contractions were found to be inhibited by about 70%.(ABSTRACT TRUNCATED AT 400 WORDS