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MSX-3

From Wikipedia, the free encyclopedia
Selective adenosine A2A receptor antagonist used in scientific research

Pharmaceutical compound
MSX-3
Clinical data
Drug classAdenosineA2A receptorantagonist
Identifiers
  • 3-[8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-2,6-dioxo-1-prop-2-ynylpurin-3-yl]propyl dihydrogen phosphate
CAS Number
PubChemCID
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 aselectiveadenosineA2A receptorantagonist used inscientific research.[1][2] Similarly toMSX-4, it is awater-solubleesterprodrug ofMSX-2.[2][3][4]

Medicinal chemistry

[edit]

MSX-3, MSX-4, and MSX-2 arexanthines and arederivatives of thenon-selectiveadenosine receptor antagonistcaffeine.[5][6] MSX-2 has been extensively studied due to its highaffinity andselectivity 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 aphosphate ester prodrug of MSX-2 that is suited best forintravenous administration and not fororal administration, MSX-4 is anamino acid ester (L-valine) prodrug of MSX-2 that can be orally administered.[2][7]

Pharmacology

[edit]

MSX-2 has 500-fold higher affinity for the adenosine A2A receptor over the adenosineA1 receptor, 580-fold higher affinity for the adenosine A2A receptor over the adenosineA2B receptor, and is inactive at the adenosineA3 receptor.[5][6][8]

MSX-3 itself also showed some affinity for theadenosine receptors, but this may have just been due todegradation byphosphatases in thein vitro system.[6]

Animal studies

[edit]

MSX-3 showspro-motivational effects in animals.[1][9] Specifically, although it showed no effect on its own, the drug reverses theeffort-related deficits induced by thedopamine depleting agenttetrabenazine (TBZ), thedopamineD2 receptorantagonistshaloperidol andeticlopride, and theproinflammatory cytokinesinterleukin-6 andinterleukin-1β.[1][9][10][11][12][13]

Conversely, it only mildly attenuates the motivational deficits induced by the dopamineD1 receptor antagonistecopipam (SCH-39166).[10][14]

History

[edit]

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

References

[edit]
  1. ^abcSalamone 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. ^abcdeMüller 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. ^abMüller 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. ^abHauber 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. ^abcde 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. ^abcYuzlenko 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. ^abVollmann 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. Retrieved23 September 2024.
  9. ^abLópez-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. ^abSalamone 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.
Receptor
(ligands)
P0 (adenine)
P1
(adenosine)
P2
(nucleotide)
P2X
(ATPTooltip Adenosine triphosphate)
P2Y
Transporter
(blockers)
CNTsTooltip Concentrative nucleoside transporters
ENTsTooltip Equilibrative nucleoside transporters
PMATTooltip Plasma membrane monoamine transporter
Enzyme
(inhibitors)
XOTooltip Xanthine oxidase
Others
Others
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