MSX-3

MSX-3
Clinical data
Drug classAdenosine A2A receptor antagonist
Identifiers
  • 3-[8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-2,6-dioxo-1-prop-2-ynylpurin-3-yl]propyl dihydrogen phosphate
CAS Number
PubChem CID
ChemSpider
UNII
ChEMBL
Chemical and physical data
FormulaC21H23N4O7P
Molar mass474.410 g·mol−1
3D model (JSmol)
  • CN1C(=NC2=C1C(=O)N(C(=O)N2CCCOP(=O)(O)O)CC#C)/C=C/C3=CC(=CC=C3)OC
  • InChI=1S/C21H23N4O7P/c1-4-11-25-20(26)18-19(24(21(25)27)12-6-13-32-33(28,29)30)22-17(23(18)2)10-9-15-7-5-8-16(14-15)31-3/h1,5,7-10,14H,6,11-13H2,2-3H3,(H2,28,29,30)/b10-9+
  • Key:DUCGTTGSVYZHJS-MDZDMXLPSA-N

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

Medicinal chemistry

MSX-3, MSX-4, and MSX-2 are xanthines and are derivatives of the non-selective adenosine receptor antagonist caffeine. 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.

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.

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.

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.

Animal studies

MSX-3 shows pro-motivational effects in animals. 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.

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

History

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

References

  1. 1 2 3 Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE (October 2018). "The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation". Pharmacological Reviews. 70 (4): 747–762. doi:10.1124/pr.117.015107. PMC 6169368. PMID 30209181.
  2. 1 2 3 4 5 Müller CE (November 2009). "Prodrug approaches for enhancing the bioavailability of drugs with low solubility". Chemistry & Biodiversity. 6 (11): 2071–2083. doi:10.1002/cbdv.200900114. PMID 19937841.
  3. 1 2 Müller CE, Sauer R, Maurinsh Y, Huertas R, Fülle F, Klotz KN, et al. (1998). "A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand". Drug Development Research. 45 (3–4): 190–197. doi:10.1002/(SICI)1098-2299(199811/12)45:3/4<190::AID-DDR16>3.0.CO;2-A. ISSN 0272-4391.
  4. 1 2 Hauber W, Nagel J, Sauer R, Müller CE (June 1998). "Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen". NeuroReport. 9 (8): 1803–1806. doi:10.1097/00001756-199806010-00024. PMID 9665604.
  5. 1 2 3 de Lera Ruiz M, Lim YH, Zheng J (May 2014). "Adenosine A2A receptor as a drug discovery target". Journal of Medicinal Chemistry. 57 (9): 3623–3650. doi:10.1021/jm4011669. PMID 24164628.
  6. 1 2 3 Yuzlenko O, Kieć-Kononowicz K (2006). "Potent adenosine A1 and A2A receptors antagonists: recent developments". Current Medicinal Chemistry. 13 (30): 3609–3625. doi:10.2174/092986706779026093. PMID 17168726.
  7. 1 2 Vollmann K, Qurishi R, Hockemeyer J, Müller CE (February 2008). "Synthesis and properties of a new water-soluble prodrug of the adenosine A 2A receptor antagonist MSX-2". Molecules. 13 (2): 348–359. doi:10.3390/molecules13020348. PMC 6244838. PMID 18305423.
  8. ↑ Khayat MT, Hanif A, Geldenhuys WJ, Nayeem MA (2019). "Adenosine Receptors and Drug Discovery in the Cardiovascular System". In Choudhary MI (ed.). Frontiers in Cardiovascular Drug Discovery: Volume 4. Amazon Digital Services LLC - Kdp. pp. 16–64. ISBN 978-1-68108-400-8. Retrieved 23 September 2024.
  9. 1 2 López-Cruz L, Salamone JD, Correa M (2018). "Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression". Frontiers in Pharmacology. 9: 526. doi:10.3389/fphar.2018.00526. PMC 5992708. PMID 29910727.
  10. 1 2 Salamone JD, Correa M, Farrar AM, Nunes EJ, Collins LE (5 May 2010). "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. doi:10.2217/fnl.10.19. hdl:10234/35900. ISSN 1479-6708.
  11. ↑ Mott AM, Nunes EJ, Collins LE, Port RG, Sink KS, Hockemeyer J, et al. (May 2009). "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. doi:10.1007/s00213-008-1441-z. PMC 2875244. PMID 19132351.
  12. ↑ Nunes EJ, Randall PA, Estrada A, Epling B, Hart EE, Lee CA, et al. (February 2014). "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. doi:10.1007/s00213-013-3285-4. PMC 4468782. PMID 24136220.
  13. ↑ Yohn SE, Arif Y, Haley A, Tripodi G, Baqi Y, Müller CE, et al. (October 2016). "Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization". Psychopharmacology. 233 (19–20): 3575–3586. doi:10.1007/s00213-016-4392-9. PMID 27497935.
  14. ↑ Worden LT, Shahriari M, Farrar AM, Sink KS, Hockemeyer J, Müller CE, et al. (April 2009). "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. doi:10.1007/s00213-008-1396-0. PMC 2875246. PMID 19048234.