5-HT2B receptor

5-Hydroxytryptamine receptor 2B (5-HT_2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the ''HTR2B'' gene. 5-HT_2B is a member of the 5-HT₂ receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).

Tissue distribution and function

First discovered in the stomach of rats, 5-HT_2B was challenging to characterize initially because of its structural similarity to the other 5-HT₂ receptors, particularly 5-HT_2C. The 5-HT₂ receptors (of which the 5-HT_2B receptor is a subtype) mediate many of the central and peripheral physiologic functions of serotonin. Cardiovascular effects include contraction of blood vessels and shape changes in platelets; central nervous system (CNS) effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenic substituted amphetamines. The 5-HT_2B receptor is expressed in several areas of the CNS, including the dorsal hypothalamus, frontal cortex, medial amygdala, and meninges. However, it is most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.

The 5-HT_2B receptor subtype is involved in:
* CNS: inhibition of serotonin and dopamine uptake, behavioural effects
* Vascular: pulmonary vasoconstriction
* Cardiac: The 5-HT_2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT_2B receptor null mice. Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts, with chronic overstimulation leading to valvulopathy. These receptors are also overexpressed in human failing heart and antagonists of 5-HT_2B receptors were uncovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.
* Serotonin transporter: 5-HT_2B receptors regulate serotonin release via the serotonin transporter, and are important both to normal physiological regulation of serotonin levels in blood plasma, and with the abnormal acute serotonin release produced by drugs such as MDMA. Surprisingly however 5-HT_2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels, despite its role in modulating serotonin release.

Clinical significance

5-HT_2B receptors have been strongly implicated in causing drug-induced valvular heart disease. The Fen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT_2B stimulation. Today, 5-HT_2B agonism is considered a toxicity signal precluding further clinical development of a compound.

Ligands

The structure of the 5-HT_2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.; As of 2009, few highly selective 5-HT_2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT_2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT_2B agonists, and the lack of clear therapeutic application for 5-HT_2B antagonists, but there is still a need for selective ligands for scientific research.

Agonists

;Selective
* BW-723C86: fair functional subtype selectivity; almost full agonist. Anxiolytic ''in vivo''.
* Ro60-0175 functionally selective over 5-HT_2A, potent agonist at both 5-HT_2B/C
* VER-3323: selective for 5-HT_2B/C over 5-HT_2A
* α-Methyl-5-HT - moderately selective over 5-HT_2A/C
* 6-APB
* LY-266,097 - biased partial agonist in favor of G_q protein, no β-arrestin2 recruitment

;
;Non-selective
* Guanfacine - an α_2A agonist, but has 5-HT_2B agonistic activity at therapeutic concentrations.
* MDMA
* MDA
* MEM
* Pergolide
* Cabergoline
* Norfenfluramine
* Chlorphentermine
* Aminorex
* Bromo-dragonfly
* DMT
* 5-MeO-DMT
* LSD - About equal affinity for human cloned 5-HT_2B and 5-HT_2A receptors.
* psilocin
*Xylometazoline
* Oxymetazoline
* Quinidine
*Ropinirole
* Fenoldopam
* Lorcaserin
*Methylergonovine
*Ergotamine
* Ergonovine

Antagonists

* Agomelatine - primarily a melatonin Mt1/Mt2 receptor agonist, with a less potent antagonism of 5-HT_2B and 5-HT_2C.
* Amisulpride
* Aripiprazole
* Cariprazine
* Clozapine
* Cyproheptadine
* mCPP (in humans)
* Sarpogrelate: a mixed 5-HT_2A/B antagonist
* Lisuride: a dopamine agonist of the ergoline class, that is also a 5-HT_2B antagonist and a dual 5-HT_2A/C agonist
* Tegaserod: primarily a 5-HT₄ agonist, but also a 5-HT_2B antagonist
* RS-127,445: high affinity; subtype selective (1000x), selective over at least eight other 5-HTR types; orally bioavailable.
*Metadoxine: a 5ht_2b antagonist and GABA-activity modulator
* SDZ SER-082: a mixed 5-HT_2B/C antagonist
* Promethazine
* EGIS-7625: high selectivity over 5-HT_2A
* PRX-08066
* SB-200,646
* SB-204,741
* SB-206,553: mixed 5-HT_2B/C antagonist and PAM at α₇ nAChR
* SB-215,505
* SB-228,357
*Terguride is an oral, potent antagonist of 5-HT2B and 5-HT2A receptors.
* LY-266,097
* LY-272,015

Possible applications

5-HT_2B antagonists have previously been proposed as treatment for migraine headaches, and RS-127,445 was trialled in humans up to Phase I for this indication, but development was not continued. More recent research has focused on possible application of 5-HT_2B antagonists as treatments for chronic heart disease. Research claims serotonin 5-HT_2B receptors have effect on liver regeneration. Antagonism of 5-HT_2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.

See also

* 5-HT receptor

References

Further reading

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External links

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{{DEFAULTSORT:5-Ht2b Receptor
Serotonin receptors