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VU0530244

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VU0530244
Clinical data
Other namesVU-0530244
Drug classSelective peripherally restricted serotonin 5-HT2B receptor antagonist
Identifiers
  • [5-(4-fluorophenyl)-2-methylpyrazol-3-yl]-[3-(6-methyl-1H-benzimidazol-2-yl)azetidin-1-yl]methanone
CAS Number
PubChem CID
ChemSpider
Chemical and physical data
FormulaC22H20FN5O
Molar mass389.434 g·mol−1
3D model (JSmol)
  • CC1=CC2=C(C=C1)N=C(N2)C3CN(C3)C(=O)C4=CC(=NN4C)C5=CC=C(C=C5)F
  • InChI=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)
  • Key: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.[3] They were identified via high-throughput screening (HTS).[3]

The affinity (IC50Tooltip half-maximal inhibitory concentration) of VU0530244 for the serotonin 5-HT2B receptor was found to be 17.3 nM.[3] Its affinity (IC50) values at the serotonin 5-HT2A and 5-HT2C receptors were greater than 10,000 nM (>578-fold less than for the serotonin 5-HT2B receptor).[3] The drug is predicted to be a robust P-glycoprotein substrate and hence is expected to have very limited blood–brain barrier permeability.[3]

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][3] 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][3] Such potential side effects can be avoided with the use of peripherally restricted serotonin 5-HT2B receptor antagonists.[3]

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.[1][2]

References

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