5-Hydroxytryptamine receptor 2B (5-HT2B) also known as serotonin receptor 2B is a protein that in humans is encoded by the HTR2B gene. 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT).
The 5-HT2 receptors (of which the 5-HT2B 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-HT2B receptor subtype is involved in:
CNS: presynaptic inhibition, behavioural effects
Vascular: pulmonary vasoconstriction
Cardiac: The 5-HT2B receptor regulates cardiac structure and functions as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice. The 5-HT2B receptor stimulation can also lead to pathological proliferation of cardiac valves fibroblasts, which with chronic overstimulation of 5-HT2B can lead to a severe valvulopathy. Moreover, 5-HT2B receptors were recently shown to be overexpressed in human failing heart and antagonists of 5-HT2B receptors were uncovered to prevent both angiotensin II or beta-adrenergic agonist-induced pathological cardiac hypertrophy in mouse.
Serotonin transporter: 5-HT2B 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-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels, despite its role in modulating serotonin release.
5-HT2B 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-HT2B receptor was recently solved in complex with the valvulopathogenic drug ergotamine.
Ligands
As of 2009, few highly selective 5-HT2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant 5-HT2C binding. Research in this area has been limited due to the cardiotoxicity of 5-HT2B agonists, and the lack of clear therapeutic application for 5-HT2B antagonists, but there is still a need for selective ligands for scientific research.
Selective
BW-723C86: fair functional subtype selectivity; almost full agonist. Anxiolytic in vivo.
Ro60-0175 functionally selective over 5-HT2A, potent agonist at both 5-HT2B/C
VER-3323: selective for 5-HT2B/C over 5-HT2A
α-Methyl-5-HT - moderately selective over 5-HT2A/C
6-APB
psilocin
Non-selective
Guanfacine - an α2A agonist, but has 5-HT2B 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-HT2B and 5-HT2A receptors.
Agomelatine - primarily a melatonin Mt1/Mt2 receptor agonist, with a less potent antagonism of 5-HT2B and 5-HT2C.
Aripiprazole
Sarpogrelate: a mixed 5-HT2A/B antagonist
Lisuride: a dopamine agonist of the ergoline class, that is also a 5-HT2B antagonist and a dual 5-HT2A/C agonist
Tegaserod: primarily a 5-HT4 agonist, but also a 5-HT2B antagonist
RS-127,445: high affinity; subtype selective (1000x), selective over at least eight other 5-HTR types; orally bioavailable.
Metadoxine: a 5ht2b antagonist and GABA-activity modulator
SDZ SER-082: a mixed 5-HT2B/C antagonist
EGIS-7625: high selectivity over 5-HT2A
PRX-08066
SB-200,646
SB-204,741
SB-206,553: mixed 5-HT2B/C antagonist and PAM at α7 nAChR
SB-215,505
SB-228,357
LY-266,097
LY-272,015
5-HT2B 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-HT2B antagonists as treatments for chronic heart disease. Research claims serotonin 5-HT2B receptors have effect on liver regeneration.
