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 (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 (CNS) 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 (PNS) 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 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 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.
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.
- Agomelatine - primarily a melatonin Mt1/Mt2 receptor agonist, with a less potent antagonism of 5-HT2B and 5-HT2C.
- mCPP (in humans)
- 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 5-HT2B antagonist and GABA-activity modulator 
- SDZ SER-082: a mixed 5-HT2B/C antagonist
- EGIS-7625: high selectivity over 5-HT2A
- SB-206,553: mixed 5-HT2B/C antagonist and PAM at α7 nAChR
- Terguride is an oral, potent antagonist of 5-HT2A and 5-HT2B receptors.
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.