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VU0530244

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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]

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

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]

See also

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References

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  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 36930852.89-96&rft.date=2023-04&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122230#id-name=PMC&rft_id=info:pmid/36930852&rft_id=info:doi/10.1089/adt.2022.116&rft.aulast=Bender&rft.aufirst=AM&rft.au=Valentine, MS&rft.au=Bauer, JA&rft.au=Days, E&rft.au=Lindsley, CW&rft.au=Merryman, WD&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10122230&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 28676029.86-104&rft.date=2017&rft_id=info:doi/10.2174/1871529X17666170703115111&rft_id=info:pmid/28676029&rft.aulast=Padhariya&rft.aufirst=K&rft.au=Bhandare, R&rft.au=Canney, D&rft.au=Velingkar, V&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 30208338.33-42&rft.date=2019-02&rft_id=info:doi/10.1016/j.phrs.2018.09.009&rft_id=info:pmid/30208338&rft.aulast=Ayme-Dietrich&rft.aufirst=E&rft.au=Lawson, R&rft.au=Da-Silva, S&rft.au=Mazzucotelli, JP&rft.au=Monassier, L&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 37584406.11027-11039&rft.date=2023-08&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073569#id-name=PMC&rft_id=info:pmid/37584406&rft_id=info:doi/10.1021/acs.jmedchem.3c01178&rft.aulast=Bender&rft.aufirst=AM&rft.au=Parr, LC&rft.au=Livingston, WB&rft.au=Lindsley, CW&rft.au=Merryman, WD&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11073569&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 28757154.143-155&rft.date=2018-01&rft_id=info:doi/10.1016/j.pharmthera.2017.07.014&rft_id=info:pmid/28757154&rft.aulast=Devroye&rft.aufirst=C&rft.au=Cathala, A&rft.au=Piazza, PV&rft.au=Spampinato, U&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 19505264.317-329&rft.date=2009-05&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695569#id-name=PMC&rft_id=info:pmid/19505264&rft_id=info:doi/10.1517/14740330902931524&rft.aulast=Rothman&rft.aufirst=RB&rft.au=Baumann, MH&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2695569&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  9. ^ Elangbam CS (October 2010). "Drug-induced valvulopathy: an update". Toxicologic Pathology. 38 (6): 837–848. doi:10.1177/0192623310378027. PMID 20716786.837-848&rft.date=2010-10&rft_id=info:doi/10.1177/0192623310378027&rft_id=info:pmid/20716786&rft.aulast=Elangbam&rft.aufirst=CS&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 17017961.1845-1859&rft.date=2006&rft_id=info:doi/10.2174/156802606778249766&rft_id=info:pmid/17017961&rft.aulast=Rothman&rft.aufirst=RB&rft.au=Baumann, MH&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 21440001.146-157&rft.date=2011-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179857#id-name=PMC&rft_id=info:pmid/21440001&rft_id=info:doi/10.1016/j.pharmthera.2011.03.008&rft.aulast=Hutcheson&rft.aufirst=JD&rft.au=Setola, V&rft.au=Roth, BL&rft.au=Merryman, WD&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179857&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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.e303 - e310&rft.date=2013-09&rft_id=info:doi/10.1016/j.lpm.2013.07.005&rft_id=info:pmid/23972547&rft.aulast=Seferian&rft.aufirst=A&rft.au=Chaumais, MC&rft.au=Savale, L&rft.au=Günther, S&rft.au=Tubert-Bitter, P&rft.au=Humbert, M&rft.au=Montani, D&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 37581427.881-883&rft.date=2023&rft_id=info:doi/10.1080/14740338.2023.2248883&rft_id=info:pmid/37581427&rft.aulast=McIntyre&rft.aufirst=RS&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 37572027.876-890&rft.date=2023-09&rft_id=info:doi/10.1177/02698811231190865&rft_id=info:pmid/37572027&rft.aulast=Tagen&rft.aufirst=M&rft.au=Mantuani, D&rft.au=van Heerden, L&rft.au=Holstein, A&rft.au=Klumpers, LE&rft.au=Knowles, R&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 38214279.217-224&rft.date=2024-03&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10944580#id-name=PMC&rft_id=info:pmid/38214279&rft_id=info:doi/10.1177/02698811231225609&rft.aulast=Rouaud&rft.aufirst=A&rft.au=Calder, AE&rft.au=Hasler, G&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10944580&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 37874530.1362-1380&rft.date=2023-12&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661823#id-name=PMC&rft_id=info:pmid/37874530&rft_id=info:doi/10.1007/s43440-023-00539-4&rft.aulast=Wsół&rft.aufirst=A&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661823&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 37790801.2013-2025&rft.date=2023&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543412#id-name=PMC&rft_id=info:pmid/37790801&rft_id=info:doi/10.2147/NDT.S417676&rft.aulast=Dini&rft.aufirst=G&rft.au=Di Cara, G&rft.au=Ferrara, P&rft.au=Striano, P&rft.au=Verrotti, A&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10543412&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
  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 28806488.4123-4139&rft.date=2017-11&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680644#id-name=PMC&rft_id=info:pmid/28806488&rft_id=info:doi/10.1111/bph.13981&rft.aulast=Ayme-Dietrich&rft.aufirst=E&rft.au=Lawson, R&rft.au=Côté, F&rft.au=de Tapia, C&rft.au=Da Silva, S&rft.au=Ebel, C&rft.au=Hechler, B&rft.au=Gachet, C&rft.au=Guyonnet, J&rft.au=Rouillard, H&rft.au=Stoltz, J&rft.au=Quentin, E&rft.au=Banas, S&rft.au=Daubeuf, F&rft.au=Frossard, N&rft.au=Gasser, B&rft.au=Mazzucotelli, JP&rft.au=Hermine, O&rft.au=Maroteaux, L&rft.au=Monassier, L&rft_id=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680644&rfr_id=info:sid/en.wikipedia.org:VU0530244" class="Z3988">
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