5-Hydroxytryptamine receptor 2B (5-HT2B) also known asserotonin receptor 2B is aprotein that in humans is encoded by theHTR2Bgene.[5][6] 5-HT2B is a member of the5-HT2 receptor family that binds theneurotransmitterserotonin (5-hydroxytryptamine, 5-HT). Like all 5-HT2 receptors, the 5-HT2B receptor isGq/G11-protein coupled, leading to downstream activation ofphospholipase C.
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.[7] The 5-HT2 receptors (of which the 5-HT2B receptor is a subtype) mediate many of the central and peripheral physiologic functions ofserotonin. 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 ofhallucinogenicsubstituted amphetamines. The 5-HT2B receptor is expressed in several areas of the CNS, including the dorsal hypothalamus, frontal cortex, medial amygdala, and meninges.[8] However, its most important role is in the peripheral nervous system (PNS) where it maintains the viability and efficiency of the cardiac valve leaflets.[9]
The 5-HT2B receptor subtype is involved in:
CNS: inhibition of serotonin and dopamine uptake, behavioral effects[10]
Cardiac: The 5-HT2B receptor regulates cardiac structure and functions, as demonstrated by the abnormal cardiac development observed in 5-HT2B receptor null mice.[12] Excessive stimulation of this receptor causes pathological proliferation of cardiac valve fibroblasts,[13] with chronic overstimulation leading to valvulopathy.[14][15] 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.[16][17][18]
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,[19] and with the abnormal acute serotonin release produced by drugs such asMDMA.[10] Surprisingly, however, 5-HT2B receptor activation appears to be protective against the development ofserotonin syndrome following elevated extracellular serotonin levels,[20] despite its role in modulating serotonin release.
5-HT2B receptors have been strongly implicated in causing drug-inducedvalvular heart disease.[21][22][23] TheFen-Phen scandal in the 80s and 90s revealed the cardiotoxic effects of 5-HT2B stimulation.[24] Today, 5-HT2B agonism is considered a toxicity signal precluding further clinical development of a compound.[25]
The non-selective serotonin receptor agonistmeta-chlorophenylpiperazine (mCPP) induces migraines and this may be due to serotonin 5-HT2B receptor agonism.[26] Serotonin 5-HT2 receptor antagonists used asantimigraine agents, such asmethysergide,cyproheptadine, andpizotifen, may be producing their antimigraine effects specifically via serotonin 5-HT2B receptor antagonism.[26]
The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drugergotamine.[27] As of 2009, few highly selective 5-HT2B receptor ligands have been discovered, although numerous potent non-selective compounds are known, particularly agents with concomitant5-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.[28]
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[31][38]
BW-723C86 – 100-fold selectivity over 5-HT2A but only 3- to 10-fold selectivity over 5-HT2C,[35][40] fair functional subtype selectivity, almost full agonist, anxiolyticin vivo[41]
LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[42]
VU6067416 – modest selectivity over 5-HT2A and 5-HT2C[43]
RQ-00310941 (RQ-941) – Ki = 2.0nM, IC50 = 17nM, >2,000-fold selectivity against >60 targets, under development for medical use[75][88][89]
RS-127,445 (MT-500) – Ki = 0.3nM, >1,000-fold selectivity over 5-HT2A and 5-HT2C and numerous other targets, selective over at least eight other serotonin receptors, developed for clinical use but discontinued[75][35][77][90][68]
SB-204,741 – >135-fold selectivity over 5-HT2C and 5-HT2A[91]
BW-501C67 andxylamidine 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.[128][129][130]
5-HT2B antagonists have previously been proposed as treatment formigraine headaches, andRS-127,445 was trialled in humans up to Phase I for this indication, but development was not continued.[131] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronicheart disease.[132][133] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[134] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.
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