Chemistry:MSX-3

From HandWiki

MSX-3 is a selective adenosine A2A receptor antagonist used in scientific research.[1][2] Similarly to MSX-4, it is a water-soluble ester prodrug of MSX-2.[2][3][4]

Medicinal chemistry

MSX-3, MSX-4, and MSX-2 are xanthines and are derivatives of the non-selective adenosine receptor antagonist caffeine.[5][6] MSX-2 has been extensively studied due to its high affinity and selectivity for the adenosine A2A receptor, but use of MSX-2 itself has been limited by its poor water solubility.[5][2]

Whereas MSX-3 is a phosphate ester prodrug of MSX-2 that is suited best for intravenous administration and not for oral administration, MSX-4 is an amino acid ester (L-valine) prodrug of MSX-2 that can be orally administered.[2][7]

Pharmacology

MSX-2 has 500-fold higher affinity for the adenosine A2A receptor over the adenosine A1 receptor, 580-fold higher affinity for the adenosine A2A receptor over the adenosine A2B receptor, and is inactive at the adenosine A3 receptor.[5][6][8]

MSX-3 itself also showed some affinity for the adenosine receptors, but this may have just been due to degradation by phosphatases in the in vitro system.[6]

Animal studies

MSX-3 shows pro-motivational effects in animals.[1][9] Specifically, although it showed no effect on its own, the drug reverses the effort-related deficits induced by the dopamine depleting agent tetrabenazine (TBZ), the dopamine D2 receptor antagonists haloperidol and eticlopride, and the proinflammatory cytokines interleukin-6 and interleukin-1β.[1][9][10][11][12][13]

Conversely, it only mildly attenuates the motivational deficits induced by the dopamine D1 receptor antagonist ecopipam (SCH-39166).[10][14]

History

MSX-3 was first described in the scientific literature by 1998.[3][4] A similar agent, MSX-4, was subsequently described by 2008.[2][7]

References

  1. ↑ 1.0 1.1 1.2 "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacological Reviews 70 (4): 747–762. October 2018. doi:10.1124/pr.117.015107. PMID 30209181. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 "Prodrug approaches for enhancing the bioavailability of drugs with low solubility". Chemistry & Biodiversity 6 (11): 2071–2083. November 2009. doi:10.1002/cbdv.200900114. PMID 19937841. 
  3. ↑ 3.0 3.1 "A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand". Drug Development Research 45 (3–4): 190–197. 1998. doi:10.1002/(SICI)1098-2299(199811/12)45:3/4<190::AID-DDR16>3.0.CO;2-A. ISSN 0272-4391. 
  4. ↑ 4.0 4.1 "Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen". NeuroReport 9 (8): 1803–1806. June 1998. doi:10.1097/00001756-199806010-00024. PMID 9665604. 
  5. ↑ 5.0 5.1 5.2 "Adenosine A2A receptor as a drug discovery target". Journal of Medicinal Chemistry 57 (9): 3623–3650. May 2014. doi:10.1021/jm4011669. PMID 24164628. 
  6. ↑ 6.0 6.1 6.2 "Potent adenosine A1 and A2A receptors antagonists: recent developments". Current Medicinal Chemistry 13 (30): 3609–3625. 2006. doi:10.2174/092986706779026093. PMID 17168726. 
  7. ↑ 7.0 7.1 "Synthesis and properties of a new water-soluble prodrug of the adenosine A 2A receptor antagonist MSX-2". Molecules 13 (2): 348–359. February 2008. doi:10.3390/molecules13020348. PMID 18305423. 
  8. ↑ "Adenosine Receptors and Drug Discovery in the Cardiovascular System". Frontiers in Cardiovascular Drug Discovery: Volume 4. Amazon Digital Services LLC - Kdp. 2019. pp. 16–64. ISBN 978-1-68108-400-8. https://books.google.com/books?id=R6SXDwAAQBAJ&pg=PA16. Retrieved 23 September 2024. 
  9. ↑ 9.0 9.1 "Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression". Frontiers in Pharmacology 9: 526. 2018. doi:10.3389/fphar.2018.00526. PMID 29910727. 
  10. ↑ 10.0 10.1 "Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation". Future Neurology 5 (3): 377–392. 5 May 2010. doi:10.2217/fnl.10.19. ISSN 1479-6708. 
  11. ↑ "The adenosine A2A antagonist MSX-3 reverses the effects of the dopamine antagonist haloperidol on effort-related decision making in a T-maze cost/benefit procedure". Psychopharmacology 204 (1): 103–112. May 2009. doi:10.1007/s00213-008-1441-z. PMID 19132351. 
  12. ↑ "Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task". Psychopharmacology 231 (4): 727–736. February 2014. doi:10.1007/s00213-013-3285-4. PMID 24136220. 
  13. ↑ "Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization". Psychopharmacology 233 (19–20): 3575–3586. October 2016. doi:10.1007/s00213-016-4392-9. PMID 27497935. 
  14. ↑ "The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists". Psychopharmacology 203 (3): 489–499. April 2009. doi:10.1007/s00213-008-1396-0. PMID 19048234. 



Retrieved from "https://handwiki.org/wiki/index.php?title=Chemistry:MSX-3&oldid=4032872"