5-HT2B receptor
Mammalian protein found in Homo sapiens From Wikipedia, the free encyclopedia
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][6] 5-HT2B is a member of the 5-HT2 receptor family that binds the neurotransmitter serotonin (5-hydroxytryptamine, 5-HT). 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
Summarize
Perspective
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 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.[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]
- Vascular: pulmonary vasoconstriction[11]
- 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 as MDMA.[10] Surprisingly, however, 5-HT2B receptor activation appears to be protective against the development of serotonin syndrome following elevated extracellular serotonin levels,[20] despite its role in modulating serotonin release.
Clinical significance
5-HT2B receptors have been strongly implicated in causing drug-induced valvular heart disease.[21][22][23] The Fen-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]
Ligands
Summarize
Perspective
The structure of the 5-HT2B receptor was resolved in a complex with the valvulopathogenic drug ergotamine.[26] 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.[27]
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[30][37]
- α-Methylserotonin – ~10-fold selectivity over 5-HT2A and 5-HT2C[34][38][36]
- BW-723C86 – 100-fold selectivity over 5-HT2A but only 3- to 10-fold selectivity over 5-HT2C,[34][39] fair functional subtype selectivity, almost full agonist, anxiolytic in vivo[40]
- LY-266,097 – biased partial agonist in favor of Gq protein, no β-arrestin2 recruitment[41]
- VU6067416 – modest selectivity over 5-HT2A and 5-HT2C[42]
Non-selective
- 25C-NBOMe[30][43]
- 25I-NBOMe[30][43]
- 2C-B[30][43]
- 2C-B-FLY[30][44]
- 2C-C[30][43]
- 2C-D[30][43]
- 2C-E[30][43]
- 2C-I[30][43]
- 4-Methylamphetamine[30]
- 5-APB[30][45][37]
- 5-APDB[30]
- 5-Carboxamidotryptamine[36]
- 5-MAPB[45]
- 6-APB[37]
- 6-APDB[30]
- 6-MAPB[45]
- 5-MeO-αMT[30][32]
- 5-MeO-DiPT
- 5-MeO-DMT[42]
- 5-MeO-MiPT[30][32]
- AL-38022A[46]
- Aminorex (weakly)[47][48]
- Ariadne[49]
- Benfluorex[50]
- Bromo-dragonfly[44][51][52]
- Bromocriptine[53]
- Cabergoline[54][35]
- Chlorphentermine (very weakly)[47]
- CYB210010 (2C-T-TFM)[55][56]
- Dexfenfluramine[57]
- Dexnorfenfluramine[57]
- Dihydroergocryptine[58]
- Dihydroergotamine[54][59]
- DiPT[30][32]
- DOB[30][36]
- DOC[30]
- DOET[60]
- DOI[30][36][35]
- DOM[30][60]
- Ergometrine (ergonovine)[54]
- Ergotamine[54][57][35]
- Fenfluramine[57][35]
- Fenoldopam[35]
- Guanfacine – an α2A-adrenergic agonist, but has 5-HT2B agonistic activity at therapeutic concentrations[35][61]
- Levofenfluramine[57]
- Levonorfenfluramine[57]
- Lorcaserin[54]
- LSD – about equal affinity for human cloned 5-HT2B and 5-HT2A receptors[62][32][63]
- LSM-775[64]
- mCPP (in humans; weak partial agonist)[57][36]
- MDA[30][65]
- MDMA[33][65]
- MEM[66]
- Mescaline[33]
- Methylergometrine (methylergonovine)[54][57][35]
- Methysergide (antagonist in some studies)[57][35][67]
- Naphthylaminopropane[68]
- Norfenfluramine[57][35][39]
- ORG-12962[36]
- ORG-37684[67]
- Oxymetazoline[35]
- Pergolide[54][35][69]
- PNU-22394
- Psilocin[62][63]
- Psilocybin[63]
- Quipazine (weak partial agonist)[36]
- Ro60-0175 – functionally selective over 5-HT2A, potent agonist at both 5-HT2B/C[34][39]
- Ropinirole[35]
- Quinidine[35]
- TFMPP (weak partial agonist)[36]
- VER-3323 – mixed 5-HT2C and 5-HT2B agonist with weaker 5-HT2A affinity[67]
- Xylometazoline[35]
Peripherally selective
Inactive
A number of notable drugs appear to be inactive or very weak as serotonin 5-HT2B receptor agonists, at least in vitro.[30] These include the stimulants and/or entactogens dextroamphetamine, dextromethamphetamine, 4-fluoroamphetamine, 4-fluoromethamphetamine, phentermine, methylone, mephedrone, MDAI, and MMAI, among others.[30][47][37][71][72][73] 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.[63][30][32]
Antagonists
Selective
- 5-HCPC[74][75]
- 5-HPEC (weak)[74]
- 5-HPPC[74]
- AM1125[74]
- AM1476[74]
- BF-1 – derived from pimethixene[74][76][77]
- EGIS-7625 – high selectivity over 5-HT2A[76][78][79]
- EXT5 – highly selective[74][80]
- EXT9 – somewhat selective[74][80]
- LY-23,728[81]
- LY-266,097 – pKi = 9.7, 100-fold selectivity over 5-HT2A and 5-HT2C[34][81]
- LY-272,015 – fairly selective and highly potent[34]
- LY-287,375[81][82]
- MRS7925 – substantially selective over 5-HT2A and 5-HT2C but minimal selectivity over the adenosine A1 receptor[83]
- MRS8209[84]
- MW071 (MW01-8-071HAB) – non-MAOI minaprine analogue[85]
- MW073 – highly selective, orally bioavailable[86]
- PRX-08066 – Ki ≈ 1.7 nM, >100-fold selectivity[74][76][34]
- RQ-00310941 (RQ-941) – Ki = 2.0 nM, IC50 = 17 nM, >2,000-fold selectivity against >60 targets, under development for medical use[74][87][88]
- RS-127,445 (MT-500) – Ki = 0.3 nM, >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[74][34][76][89][67]
- SB-204,741 – >135-fold selectivity over 5-HT2C and 5-HT2A[90]
- SB-215,505 – mixed 5-HT2B and 5-HT2C antagonist[34][76][91]
- VU6047534 – weak partial agonist or antagonist, peripherally selective in mice but not humans[92][93]
Non-selective
- 2-Bromo-LSD (BOL-148; bromolysergide)[94]
- (–)-MBP – 5-HT2A antagonist, 5-HT2B inverse agonist, and 5-HT2C agonist[95]
- Agomelatine – primarily a melatonin MT1/MT2 receptor agonist, with a less potent antagonism of 5-HT2B and 5-HT2C[96]
- AMAP102 (AMAP-102) – 5-HT2B and 5-HT2C antagonist[74][97]
- Amesergide (LY-237733)
- Amisulpride
- Amitriptyline
- Apomorphine
- Aripiprazole[34]
- Asenapine[34]
- BMB-201 – and active form BMB-39a[98]
- Brexpiprazole
- Brilaroxazine
- C-122[74][34]
- Cariprazine[34][99]
- Chlorpromazine
- Clozapine[67][34]
- Cyproheptadine
- Desmethylclozapine (NDMC; norclozapine)
- Ibogainalog[100]
- ITI-1549[101]
- KB-128 – 5-HT2A and 5-HT2B antagonist and 5-HT2C agonist[102]
- Lisuride – a dopamine agonist of the ergoline class, that is also a 5-HT2B antagonist[103] and a dual 5-HT2A/C agonist[104]
- Lurasidone
- LY-53857
- Mesulergine[67]
- Metadoxine – a 5-HT2B antagonist and GABA-activity modulator[105]
- Metergoline[67]
- Metitepine (methiothepin)[67]
- Mianserin[67]
- Molindone[106][107]
- N-Methylamisulpride
- Nantenine[74]
- Naphthylpiperazine (1-NP)
- Olanzapine
- Pimethixene[77]
- Pipamperone
- Pizotifen (pizotyline)
- Promethazine[108]
- Quetiapine
- Rauwolscine[34]
- Risperidone
- Ritanserin[34][67]
- SB-200,646 – 5-HT2B/5-HT2C antagonist, selective over 5-HT2A
- SB-206,553 – mixed 5-HT2B and 5-HT2C antagonist and PAM at α7 nAChR[76][109][110][67]
- SB-221,284 – 5-HT2B/5-HT2C antagonist[38][67]
- SB-228,357 – 5-HT2B/5-HT2C antagonist
- SDZ SER-082 – a mixed 5-HT2B/C antagonist
- Spiperone
- Tabernanthalog (TBG; DLX-007)[100]
- Tegaserod – primarily a 5-HT4 agonist, but also a 5-HT2B antagonist[111][112]
- Terguride – an oral, potent antagonist of 5-HT2A and 5-HT2B receptors[76][34]
- Trazodone[67]
- Vabicaserin[113]
- Viloxazine – weak 5-HT2B antagonist and 5-HT2C agonist[114][115]
- Xanomeline – similar affinity as for muscarinic acetylcholine receptors[92][116][117]
- Yohimbine[34]
- Zalsupindole (DLX-001; AAZ-A-154)[118]
- Ziprasidone
Unknown or unsorted selectivity
Peripherally selective
- Sarpogrelate (MCI-9042, LS-187,118) – non-selective 5-HT2 antagonist, but ~2 orders of magnitude lower affinity at 5-HT2B than at 5-HT2A[120][121]
- VU0530244 – 5-HT2B-selective[122]
- VU0631019 – 5-HT2B-selective[122]
- VU6055320 – 5-HT2B-selective[92][93]
- Others (e.g., "compound 19c")[123]
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.[124][125][126]
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.[127] More recent research has focused on possible application of 5-HT2B antagonists as treatments for chronic heart disease.[128][129] Research claims serotonin 5-HT2B receptors have effect on liver regeneration.[130] Antagonism of 5-HT2B may attenuate fibrogenesis and improve liver function in disease models in which fibrosis is pre-established and progressive.
See also
References
Further reading
External links
Wikiwand - on
Seamless Wikipedia browsing. On steroids.