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).

Function

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 effects include neuronal sensitization to tactile stimuli and mediation of some of the effects of hallucinogenic substituted amphetamines.

The 5-HT_2B receptor subtype is involved in:

• CNS: presynaptic inhibition, 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. The 5-HT_2B receptor stimulation can also lead to pathological proliferation of cardiac valves fibroblasts, which with chronic overstimulation of 5-HT_2B can lead to a severe valvulopathy. Moreover, 5-HT_2B receptors were recently shown to be 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 also been strongly implicated in drug-induced valvular heart disease. In this context, it is generally considered to be an antitarget.

The structure of the 5-HT_2B receptor was recently solved in complex with the valvulopathogenic drug ergotamine.

Ligands

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
• psilocin - 23x greater selectivity for human cloned 5-HT_2B receptors over 5-HT_2A.

Non-selective

• Guanfacine - an α_2A agonist, but has 5-HT_2B agonistic activity at therapeutic concentrations.
• MDMA (Ecstasy)
• MDA
• MEM
• Pergolide
• Cabergoline
• Norfenfluramine
• Chlorphentermine
• Aminorex
• mCPP
• Bromo-dragonfly
• DMT
• 5-MeO-DMT
• LSD-25 - About equal affinity for human cloned 5-HT_2B and 5-HT_2A receptors.

Antagonists

• Agomelatine - primarily a melatonin Mt1/Mt2 receptor agonist, with a less potent antagonism of 5-HT_2B and 5-HT_2C.
• 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.
• SDZ SER-082: a mixed 5-HT_2B/C antagonist
• 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
• 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-HT2B receptors have effect on liver regeneration.

See also

• 5-HT receptor

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.