5-HT2B receptor


5-Hydroxytryptamine receptor 2B 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. Like all 5-HT2 receptors, the 5-HT2B receptor is Gq/G11-protein coupled, leading to downstream activation of phospholipase C.

Tissue distribution and function

First discovered in the stomach of rats, 5-HT2B was challenging to characterize initially because of its structural similarity to the other 5-HT2 receptors, particularly 5-HT2C. The 5-HT2 receptors 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 is expressed in several areas of the CNS, including the dorsal hypothalamus, frontal cortex, medial amygdala, and meninges. However, its most important role is in the peripheral nervous system where it maintains the viability and efficiency of the cardiac valve leaflets.
The 5-HT2B receptor subtype is involved in:
  • CNS: inhibition of serotonin and dopamine uptake, behavioral 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. 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-HT2B receptors were discovered 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.

Clinical significance

Valvular heart disease

5-HT2B 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-HT2B stimulation. Today, 5-HT2B agonism is considered a toxicity signal precluding further clinical development of a compound.

Migraines

The non-selective serotonin receptor agonist meta-chlorophenylpiperazine induces migraines and this may be due to serotonin 5-HT2B receptor agonism. Serotonin 5-HT2 receptor antagonists used as antimigraine agents, such as methysergide, cyproheptadine, and pizotifen, may be producing their antimigraine effects specifically via serotonin 5-HT2B receptor antagonism.

Ligands

The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine. 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.

Agonists

Endogenous

Selective

  • 6-APB – ~100-fold selectivity over the 5-HT2A and 5-HT2C receptors, ≥32-fold selectivity over monoamine release, ~12-fold selectivity over α2C-adrenergic receptor
  • α-Methylserotonin – ~10-fold selectivity over 5-HT2A and 5-HT2C
  • BW-723C86 – 100-fold selectivity over 5-HT2A but only 3- to 10-fold selectivity over 5-HT2C, fair functional subtype selectivity, almost full agonist, anxiolytic in vivo
  • LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment
  • VU6067416 – modest selectivity over 5-HT2A and 5-HT2C

Non-selective

Peripherally selective

  • AL-34662 – non-selective over 5-HT2A and 5-HT2C

Inactive

A number of notable drugs appear to be inactive or very weak as serotonin 5-HT2B receptor agonists, at least in vitro. These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others. Findings are somewhat conflicting for certain psychedelics, such as psilocin and LSD, but most studies find that these drugs are indeed potent serotonin 5-HT2B receptor agonists.

Antagonists

Selective

Non-selective

Unknown or unsorted selectivity

Peripherally selective

BW-501C67 and xylamidine are known peripherally selective antagonists of the serotonin 5-HT2 receptors, including of the serotonin 5-HT2A and 5-HT2B receptors, but their serotonin 5-HT2B receptor interactions do not appear to have been described.

Possible applications

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. Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.