MSX-3
{{Short description|Selective adenosine A2A receptor antagonist used in scientific research}}
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{{Infobox drug
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| class = Adenosine A2A receptor antagonist
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| CAS_number = 261705-79-7
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| PubChem = 10256042
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| ChemSpiderID = 8431526
| UNII = 72MRN83M4A
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| ChEMBL = 1205720
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| IUPAC_name = 3-[8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-2,6-dioxo-1-prop-2-ynylpurin-3-yl]propyl dihydrogen phosphate
| C=21 | H=23 | N=4 | O=7 | P=1
| SMILES = CN1C(=NC2=C1C(=O)N(C(=O)N2CCCOP(=O)(O)O)CC#C)/C=C/C3=CC(=CC=C3)OC
| StdInChI = 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+
| StdInChIKey = DUCGTTGSVYZHJS-MDZDMXLPSA-N
}}
MSX-3 is a selective adenosine A2A receptor antagonist used in scientific research.{{cite journal | vauthors = Salamone JD, Correa M, Ferrigno S, Yang JH, Rotolo RA, Presby RE | title = The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation | journal = Pharmacological Reviews | volume = 70 | issue = 4 | pages = 747–762 | date = October 2018 | pmid = 30209181 | pmc = 6169368 | doi = 10.1124/pr.117.015107 }}{{cite journal | vauthors = Müller CE | title = Prodrug approaches for enhancing the bioavailability of drugs with low solubility | journal = Chemistry & Biodiversity | volume = 6 | issue = 11 | pages = 2071–2083 | date = November 2009 | pmid = 19937841 | doi = 10.1002/cbdv.200900114 }} Similarly to MSX-4, it is a water-soluble ester prodrug of MSX-2.{{cite journal | vauthors = Müller CE, Sauer R, Maurinsh Y, Huertas R, Fülle F, Klotz KN, Nagel J, Hauber W | title=A2A-selective adenosine receptor antagonists: Development of water-soluble prodrugs and a new tritiated radioligand | journal=Drug Development Research | volume=45 | issue=3–4 | date=1998 | issn=0272-4391 | doi=10.1002/(SICI)1098-2299(199811/12)45:3/4<190::AID-DDR16>3.0.CO;2-A | pages=190–197}}{{cite journal | vauthors = Hauber W, Nagel J, Sauer R, Müller CE | title = Motor effects induced by a blockade of adenosine A2A receptors in the caudate-putamen | journal = NeuroReport | volume = 9 | issue = 8 | pages = 1803–1806 | date = June 1998 | pmid = 9665604 | doi = 10.1097/00001756-199806010-00024 }}
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.{{cite journal | vauthors = de Lera Ruiz M, Lim YH, Zheng J | title = Adenosine A2A receptor as a drug discovery target | journal = Journal of Medicinal Chemistry | volume = 57 | issue = 9 | pages = 3623–3650 | date = May 2014 | pmid = 24164628 | doi = 10.1021/jm4011669 }}
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.{{cite journal | vauthors = Yuzlenko O, Kieć-Kononowicz K | title = Potent adenosine A1 and A2A receptors antagonists: recent developments | journal = Current Medicinal Chemistry | volume = 13 | issue = 30 | pages = 3609–3625 | date = 2006 | pmid = 17168726 | doi = 10.2174/092986706779026093 }}{{cite book | vauthors = Khayat MT, Hanif A, Geldenhuys WJ, Nayeem MA | chapter = Adenosine Receptors and Drug Discovery in the Cardiovascular System | pages=16–64 | veditors=Choudhary MI | title=Frontiers in Cardiovascular Drug Discovery: Volume 4 | publisher=Amazon Digital Services LLC - Kdp | year=2019 | isbn=978-1-68108-400-8 | chapter-url=https://books.google.com/books?id=R6SXDwAAQBAJ&pg=PA16 | access-date=23 September 2024}}
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.{{cite journal | vauthors = López-Cruz L, Salamone JD, Correa M | title = Caffeine and Selective Adenosine Receptor Antagonists as New Therapeutic Tools for the Motivational Symptoms of Depression | journal = Frontiers in Pharmacology | volume = 9 | issue = | pages = 526 | date = 2018 | pmid = 29910727 | pmc = 5992708 | doi = 10.3389/fphar.2018.00526 | doi-access = free }} 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.{{cite journal | vauthors = Salamone JD, Correa M, Farrar AM, Nunes EJ, Collins LE | title=Role of dopamine–adenosine interactions in the brain circuitry regulating effort-related decision making: insights into pathological aspects of motivation | journal=Future Neurology | volume=5 | issue=3 | date=5 May 2010 | issn=1479-6708 | doi=10.2217/fnl.10.19 | pages=377–392| hdl=10234/35900 | hdl-access=free }}{{cite journal | vauthors = Mott AM, Nunes EJ, Collins LE, Port RG, Sink KS, Hockemeyer J, Müller CE, Salamone JD | title = 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 | journal = Psychopharmacology | volume = 204 | issue = 1 | pages = 103–112 | date = May 2009 | pmid = 19132351 | pmc = 2875244 | doi = 10.1007/s00213-008-1441-z }}{{cite journal | vauthors = Nunes EJ, Randall PA, Estrada A, Epling B, Hart EE, Lee CA, Baqi Y, Müller CE, Correa M, Salamone JD | title = Effort-related motivational effects of the pro-inflammatory cytokine interleukin 1-beta: studies with the concurrent fixed ratio 5/ chow feeding choice task | journal = Psychopharmacology | volume = 231 | issue = 4 | pages = 727–736 | date = February 2014 | pmid = 24136220 | pmc = 4468782 | doi = 10.1007/s00213-013-3285-4 }}{{cite journal | vauthors = Yohn SE, Arif Y, Haley A, Tripodi G, Baqi Y, Müller CE, Miguel NS, Correa M, Salamone JD | title = Effort-related motivational effects of the pro-inflammatory cytokine interleukin-6: pharmacological and neurochemical characterization | journal = Psychopharmacology | volume = 233 | issue = 19–20 | pages = 3575–3586 | date = October 2016 | pmid = 27497935 | doi = 10.1007/s00213-016-4392-9 }}
Conversely, it only mildly attenuates the motivational deficits induced by the dopamine D1 receptor antagonist ecopipam (SCH-39166).{{cite journal | vauthors = Worden LT, Shahriari M, Farrar AM, Sink KS, Hockemeyer J, Müller CE, Salamone JD | title = The adenosine A2A antagonist MSX-3 reverses the effort-related effects of dopamine blockade: differential interaction with D1 and D2 family antagonists | journal = Psychopharmacology | volume = 203 | issue = 3 | pages = 489–499 | date = April 2009 | pmid = 19048234 | pmc = 2875246 | doi = 10.1007/s00213-008-1396-0 }}
History
MSX-3 was first described in the scientific literature by 1998. A similar agent, MSX-4, was subsequently described by 2008.{{cite journal | vauthors = Vollmann K, Qurishi R, Hockemeyer J, Müller CE | title = Synthesis and properties of a new water-soluble prodrug of the adenosine A 2A receptor antagonist MSX-2 | journal = Molecules | volume = 13 | issue = 2 | pages = 348–359 | date = February 2008 | pmid = 18305423 | pmc = 6244838 | doi = 10.3390/molecules13020348 | doi-access = free }}