Chemistry: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]

The affinity (IC50) 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

References

  1. ↑ 1.0 1.1 "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. doi:10.1089/adt.2024.87345.rfs2023. PMID 39250303. 
  2. ↑ 2.0 2.1 Shapiro, Marissa (28 August 2024). "Emily Days wins Rosalind Franklin Society Special Award in Science for contributions to the journal ASSAY and Drug Development Technologies". https://medschool.vanderbilt.edu/basic-sciences/2024/08/28/emily-days-wins-rosalind-franklin-society-special-award-in-science-for-contributions-to-the-journal-assay-and-drug-development-technologies/. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 "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. doi:10.1089/adt.2022.116. PMID 36930852. 
  4. ↑ "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. doi:10.2174/1871529X17666170703115111. PMID 28676029. 
  5. ↑ "Serotonin contribution to cardiac valve degeneration: new insights for novel therapies?". Pharmacological Research 140: 33–42. February 2019. doi:10.1016/j.phrs.2018.09.009. PMID 30208338. 
  6. ↑ "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". Journal of Medicinal Chemistry 66 (16): 11027–11039. August 2023. doi:10.1021/acs.jmedchem.3c01178. PMID 37584406. 
  7. ↑ "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. doi:10.1016/j.pharmthera.2017.07.014. PMID 28757154. 
  8. ↑ "Serotonergic drugs and valvular heart disease". Expert Opinion on Drug Safety 8 (3): 317–329. May 2009. doi:10.1517/14740330902931524. PMID 19505264. 
  9. ↑ "Drug-induced valvulopathy: an update". Toxicologic Pathology 38 (6): 837–848. October 2010. doi:10.1177/0192623310378027. PMID 20716786. 
  10. ↑ "Therapeutic potential of monoamine transporter substrates". Current Topics in Medicinal Chemistry 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  11. ↑ "Serotonin receptors and heart valve disease--it was meant 2B". Pharmacology & Therapeutics 132 (2): 146–157. November 2011. doi:10.1016/j.pharmthera.2011.03.008. PMID 21440001. 
  12. ↑ "Drugs induced pulmonary arterial hypertension". Presse Médicale 42 (9 Pt 2): e303–e310. September 2013. doi:10.1016/j.lpm.2013.07.005. PMID 23972547. 
  13. ↑ "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. doi:10.1080/14740338.2023.2248883. PMID 37581427. 
  14. ↑ "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease". Journal of Psychopharmacology 37 (9): 876–890. September 2023. doi:10.1177/02698811231190865. PMID 37572027. 
  15. ↑ "Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins". Journal of Psychopharmacology 38 (3): 217–224. March 2024. doi:10.1177/02698811231225609. PMID 38214279. 
  16. ↑ "Cardiovascular safety of psychedelic medicine: current status and future directions". Pharmacological Reports 75 (6): 1362–1380. December 2023. doi:10.1007/s43440-023-00539-4. PMID 37874530. 
  17. ↑ "Reintroducing Fenfluramine as a Treatment for Seizures: Current Knowledge, Recommendations and Gaps in Understanding". Neuropsychiatric Disease and Treatment 19: 2013–2025. 2023. doi:10.2147/NDT.S417676. PMID 37790801. 
  18. ↑ "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. doi:10.1111/bph.13981. PMID 28806488. 



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