5-HT2b receptor

Kantor, S., Jakus, R., Balogh, B., Benko, A. Bagdy, G. (2004). Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT2B receptor by the subtype-selective antagonist SB-215505. Br. J. Pharmacol. 142, 1332-42. 

Cox, D. A. and Cohen, M. L. 5-HT2B receptor signaling in the rat stomach fundus dependence on calcium influx, calcium release and protein kinase C. Behav. Brain Res. 73 289-292,1996. 

The Emergence of Serotonin 5-HT2B Receptors as Drug Antitargets... 

Perhaps, the most significant success of receptorome screening was the implication of the serotonin 5-HT2B receptor in the VHD associated with fenfluramine use. The anorexigen fenfluramine was widely used in the 1990s as an adjunct to diet and exercise, with great success [8]. Originally, racemic fenfluramine was used with... 

Post-Receptorome Screening Data Implicate 5-HT2b Receptors 145... 

Further evidence implicating 5-HT2b receptors in drug-associated VHD came in the years following our predictions. In 2003, we used primary cultures of human heart valve interstitial cells (hVICs) to assess whether fenfluramine and/or norfenfluramine induced cell proliferation - an in vitro approximation of the proliferative lesions found in the valves of VHD patients - in a 5-HT2b receptor-dependent manner [11], Treatment of primary hVIC cultures with either fenfluramine or norfenfluramine increased biochemical indices of cell proliferation, an effect that was blocked by cotreatment with a 5-HT2b receptor-selective antagonist [11]. 

Figure 7.1 Chemical structures of VHD/PH-associated drugs that are also 5-HT2B receptor agonists. The chemical structures of all currently known VHD/PH-inducing drugs-all exhibit high-to-moderate 5-HT2B receptor agonist potency -are shown. MDMA and MDA are included as they behave similarly to VHD-associated drugs in vitro.

For fenfluramine, MDMA and methysergide, in vivo oxidation gives rise to a more potent 5-HT2B receptor agonist than the parent compound. The oxidized nitrogen is indicated by a solid arrow. Note that all drugs fall into one of the two structural classes phenylisopropylamines (top) and ergolines (bottom). 

Our studies clearly implicate 5-HT2B receptor agonism as causes of serious and potentially fatal drug side effects in humans - VHD and PH. Given the ease with... 

Da Prada, M. and Kellermann, O. (2006) Serotonin transport and serotonin transporter-mediated antidepressant recognition are controlled by 5-HT2B receptor signaling in serotonergic neuronal cells. FASEB Journal, 20 (11), 1843-1854. 

An interesting series of 3-benzazepine derivatives (including 355) have been reported to be potent and selective (over 5-HT2a and 5-HT2b receptors) 5-HT2q receptor agonists, of potential use for the treatment of obesity <2005BML1467>. 

De Lucchini S, Marracci S, Nardi I. The serotonin 5-HT2B receptor from the puffer fish Tetraodon fluviatilis cDNA cloning, genomic organization and alternatively spliced variants. Brain Res Mol Brain Res 2001 97 89-93. 

Manivet P, Schneider B, Smith JC, Choi DS, Maroteaux L, Kellermann O. The serotonin binding site of human and murine 5-HT2B receptors molecular modeling and site-directed mutagenesis. J Biol Chem 2002 277 17,170-17,178. 

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