VU0530244 explained

Width:250px
Class:Selective peripherally restricted serotonin 5-HT2B receptor antagonist
Cas Number:1396886-30-8
Pubchem:71783796
Chemspiderid:30683125
Synonyms:VU-0530244
Iupac Name:[5-(4-fluorophenyl)-2-methylpyrazol-3-yl]-[3-(6-methyl-1''H''-benzimidazol-2-yl)azetidin-1-yl]methanone
C:22
H:20
F:1
N:5
O:1
Smiles:CC1=CC2=C(C=C1)N=C(N2)C3CN(C3)C(=O)C4=CC(=NN4C)C5=CC=C(C=C5)F
Stdinchi:1S/C22H20FN5O/c1-13-3-8-17-19(9-13)25-21(24-17)15-11-28(12-15)22(29)20-10-18(26-27(20)2)14-4-6-16(23)7-5-14/h3-10,15H,11-12H2,1-2H3,(H,24,25)
Stdinchikey:JWLJKHOGMOIRDR-UHFFFAOYSA-N

VU0530244 is a potent, selective, and putatively peripherally restricted serotonin 5-HT2B receptor antagonist which was first described in 2023.[1] [2] [3] Another similar drug, VU0631019, was also described alongside VU0530244. They were identified via high-throughput screening (HTS).

The affinity of VU0530244 for the serotonin 5-HT2B receptor was found to be 17.3nM. Its affinity values at the serotonin 5-HT2A and 5-HT2C receptors were greater than 10,000nM (>578-fold less than for the serotonin 5-HT2B receptor). The drug is predicted to be a robust P-glycoprotein substrate and hence is expected to have very limited blood–brain barrier permeability.

Serotonin 5-HT2B receptor antagonists are of interest for potential use in medicine to treat pulmonary arterial hypertension, valvular heart disease, and related cardiopathies.[4] [5] [6] However, reduced serotonin 5-HT2B receptor signaling in the central nervous system has been linked to adverse effects such as impulsivity, suicidality, and sleep disturbances, among others.[7] Such potential side effects can be avoided with the use of peripherally restricted serotonin 5-HT2B receptor antagonists.

In addition, activation of serotonin 5-HT2B receptors is thought to be responsible for development of cardiac fibrosis and valvulopathy as well as pulmonary hypertension with certain serotonergic agents, including direct serotonin 5-HT2B receptor agonists like cabergoline, ergotamine, methysergide, and pergolide, serotonin releasing agents like chlorphentermine and aminorex, and dual serotonin 5-HT2B receptor agonists and serotonin releasing agents like fenfluramine, dexfenfluramine, benfluorex, and MDMA.[8] [9] [10] [11] [12] Serotonergic psychedelics like lysergic acid diethylamide (LSD) and psilocybin as well as entactogens like MDMA are also potent serotonin 5-HT2B receptor agonists, and there have been concerns about chronic administration of these and related agents in medical contexts due to possible development of cardiac and other complications.[13] [14] [15] [16] Selective serotonin 5-HT2B receptor antagonism has been found to fully prevent the cardiotoxicity of dexnorfenfluramine in rodents.[17] [18]

In 2024, the paper that described the discovery of the VU0530244 won the 2023 Rosalind Franklin Society Special Award in Science for contributions to the journal Assay and Drug Development Technologies.

See also

Notes and References

  1. ((Rosalind Franklin Society)) . Rosalind Franklin Society Proudly Announces the 2023 Award Recipient for ASSAY and Drug Development Technologies . ASSAY and Drug Development Technologies . 22 . 6 . 277 . 1 September 2024 . 39250303 . 10.1089/adt.2024.87345.rfs2023 .
  2. Web site: Shapiro . Marissa . Emily Days wins Rosalind Franklin Society Special Award in Science for contributions to the journal ASSAY and Drug Development Technologies . Vanderbilt University . 28 August 2024 . 10 November 2024.
  3. Bender AM, Valentine MS, Bauer JA, Days E, Lindsley CW, Merryman WD . Identification of Potent, Selective, and Peripherally Restricted Serotonin Receptor 2B Antagonists from a High-Throughput Screen . Assay and Drug Development Technologies . 21 . 3 . 89–96 . April 2023 . 36930852 . 10122230 . 10.1089/adt.2022.116 .
  4. Padhariya K, Bhandare R, Canney D, Velingkar V . Cardiovascular Concern of 5-HT2B Receptor and Recent Vistas in the Development of Its Antagonists . Cardiovascular & Hematological Disorders Drug Targets . 17 . 2 . 86–104 . 2017 . 28676029 . 10.2174/1871529X17666170703115111 .
  5. Ayme-Dietrich E, Lawson R, Da-Silva S, Mazzucotelli JP, Monassier L . Serotonin contribution to cardiac valve degeneration: new insights for novel therapies? . Pharmacological Research . 140 . 33–42 . February 2019 . 30208338 . 10.1016/j.phrs.2018.09.009 .
  6. Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD . 2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery . Journal of Medicinal Chemistry . 66 . 16 . 11027–11039 . August 2023 . 37584406 . 11073569 . 10.1021/acs.jmedchem.3c01178 .
  7. Devroye C, Cathala A, Piazza PV, Spampinato U . The central serotonin2B receptor as a new pharmacological target for the treatment of dopamine-related neuropsychiatric disorders: Rationale and current status of research . Pharmacology & Therapeutics . 181 . 143–155 . January 2018 . 28757154 . 10.1016/j.pharmthera.2017.07.014 .
  8. Rothman RB, Baumann MH . Serotonergic drugs and valvular heart disease . Expert Opinion on Drug Safety . 8 . 3 . 317–329 . May 2009 . 19505264 . 2695569 . 10.1517/14740330902931524 .
  9. Elangbam CS . Drug-induced valvulopathy: an update . Toxicologic Pathology . 38 . 6 . 837–848 . October 2010 . 20716786 . 10.1177/0192623310378027 .
  10. Rothman RB, Baumann MH . Therapeutic potential of monoamine transporter substrates . Current Topics in Medicinal Chemistry . 6 . 17 . 1845–1859 . 2006 . 17017961 . 10.2174/156802606778249766 .
  11. Hutcheson JD, Setola V, Roth BL, Merryman WD . Serotonin receptors and heart valve disease--it was meant 2B . Pharmacology & Therapeutics . 132 . 2 . 146–157 . November 2011 . 21440001 . 3179857 . 10.1016/j.pharmthera.2011.03.008 .
  12. Seferian A, Chaumais MC, Savale L, Günther S, Tubert-Bitter P, Humbert M, Montani D . Drugs induced pulmonary arterial hypertension . Presse Medicale . 42 . 9 Pt 2 . e303–e310 . September 2013 . 23972547 . 10.1016/j.lpm.2013.07.005 .
  13. McIntyre RS . Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents . Expert Opinion on Drug Safety . 22 . 10 . 881–883 . 2023 . 37581427 . 10.1080/14740338.2023.2248883 .
  14. Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R . The risk of chronic psychedelic and MDMA microdosing for valvular heart disease . Journal of Psychopharmacology . 37 . 9 . 876–890 . September 2023 . 37572027 . 10.1177/02698811231190865 .
  15. Rouaud A, Calder AE, Hasler G . Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins . Journal of Psychopharmacology . 38 . 3 . 217–224 . March 2024 . 38214279 . 10944580 . 10.1177/02698811231225609 .
  16. Wsół A . Cardiovascular safety of psychedelic medicine: current status and future directions . Pharmacological Reports . 75 . 6 . 1362–1380 . December 2023 . 37874530 . 10661823 . 10.1007/s43440-023-00539-4 .
  17. Dini G, Di Cara G, Ferrara P, Striano P, Verrotti A . Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding . Neuropsychiatric Disease and Treatment . 19 . 2013–2025 . 2023 . 37790801 . 10543412 . 10.2147/NDT.S417676 . free .
  18. Ayme-Dietrich E, Lawson R, Côté F, de Tapia C, Da Silva S, Ebel C, Hechler B, Gachet C, Guyonnet J, Rouillard H, Stoltz J, Quentin E, Banas S, Daubeuf F, Frossard N, Gasser B, Mazzucotelli JP, Hermine O, Maroteaux L, Monassier L . The role of 5-HT2B receptors in mitral valvulopathy: bone marrow mobilization of endothelial progenitors . British Journal of Pharmacology . 174 . 22 . 4123–4139 . November 2017 . 28806488 . 5680644 . 10.1111/bph.13981 .

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