MSX-2

MSX-2
Clinical data
Other names	3-(3-Hydroxypropyl)-7-methyl-8-(3-methoxystyryl)-1-propargylxanthine
Drug class	Adenosine A2A receptor antagonist
Identifiers
	IUPAC name 3-(3-hydroxypropyl)-8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-1-prop-2-ynylpurine-2,6-dione;
CAS Number	261717-18-4;
PubChem CID	10046145;
IUPHAR/BPS	5610;
ChemSpider	8221708;
ChEMBL	ChEMBL413079;
CompTox Dashboard (EPA)	DTXSID50434735 ;
Chemical and physical data
Formula	C21H22N4O4
Molar mass	394.431 g·mol−1
3D model (JSmol)	Interactive image;
	SMILES CN1C(=NC2=C1C(=O)N(C(=O)N2CCCO)CC#C)/C=C/C3=CC(=CC=C3)OC;
	InChI InChI=1S/C21H22N4O4/c1-4-11-25-20(27)18-19(24(21(25)28)12-6-13-26)22-17(23(18)2)10-9-15-7-5-8-16(14-15)29-3/h1,5,7-10,14,26H,6,11-13H2,2-3H3/b10-9+; Key:FWLDDFYHEQMIGG-MDZDMXLPSA-N;

MSX-2 is a selective adenosine A_2A receptor antagonist used in scientific research.^[1] It is a xanthine and a derivative of the non-selective adenosine receptor antagonist caffeine.^[1]^[2]

The affinities (K_i) of MSX-2 for the human adenosine receptors are 5.38 to 14.5 nM for the adenosine A_2A receptor, 2,500 nM for the adenosine A₁ receptor (172- to 465-fold lower than for the A_2A receptor), and >10,000 nM for the adenosine A_2B and A₃ receptors (>690-fold lower than for the A_2A receptor).^[3]^[4]

MSX-2 has poor water solubility, which has limited the use of MSX-2 itself.^[1]^[5] Water-soluble ester prodrugs of MSX-2, including MSX-3 (a phosphate ester prodrug) and MSX-4 (an amino acid ester prodrug), have been developed and used in place of MSX-2.^[1]^[5] MSX-3 is best-suited for use by intravenous administration, whereas MSX-4 can be administered by oral administration.^[5]^[6]

MSX-3 and MSX-4 reverse motivational deficits in animals and hence have the capacity to produce pro-motivational effects.^[7]^[8]^[9]

MSX-2 and MSX-3 were first described in the scientific literature by 1998.^[10]^[11] Subsequently, MSX-4 was developed and described by 2008.^[5]^[6]

References

^ ^a ^b ^c ^d 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.
^ 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.
^ 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.
^ Müller CE, Jacobson KA (May 2011). "Recent developments in adenosine receptor ligands and their potential as novel drugs". Biochim Biophys Acta. 1808 (5): 1290–1308. doi:10.1016/j.bbamem.2010.12.017. PMC 3437328. PMID 21185259.
^ ^a ^b ^c ^d 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.
^ ^a ^b 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.
^ 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.
^ 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.
^ 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.
^ Müller CE, Sauer R, Maurinsh Y, Huertas R, Fülle F, Klotz KN, Nagel J, Hauber W (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.
^ 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.

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[deLeraRuiz2014-1] 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.

[YuzlenkoKieć-Kononowicz2006-2] 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.

[KhayatHanifGeldenhuys2019-3] 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.

[MüllerJacobson2011-4] Müller CE, Jacobson KA (May 2011). "Recent developments in adenosine receptor ligands and their potential as novel drugs". Biochim Biophys Acta. 1808 (5): 1290–1308. doi:10.1016/j.bbamem.2010.12.017. PMC 3437328. PMID 21185259.

[Müller2009-5] 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.

[VollmannQurishiHockemeyer2008-6] 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.

[SalamoneCorreaFerrigno2018-7] 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.

[López-CruzSalamoneCorrea2018-8] 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.

[SalamoneCorreaFarrar2010-9] 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.

[MüllerSauerMaruinsh1998-10] Müller CE, Sauer R, Maurinsh Y, Huertas R, Fülle F, Klotz KN, Nagel J, Hauber W (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.

[HauberNagelSauer1998-11] 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.

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MSX-2

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