MSX-3

MSX-3 is a selective adenosine A_2A 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]

MSX-3

Clinical data
Drug class	Adenosine A2A receptor antagonist
Identifiers
IUPAC name 3-[8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-2,6-dioxo-1-prop-2-ynylpurin-3-yl]propyl dihydrogen phosphate
CAS Number	261705-79-7
PubChem CID	10256042
ChemSpider	8431526
UNII	72MRN83M4A
ChEMBL	ChEMBL1205720
Chemical and physical data
Formula	C21H23N4O7P
Molar mass	474.410 g·mol−1
3D model (JSmol)	Interactive image
SMILES CN1C(=NC2=C1C(=O)N(C(=O)N2CCCOP(=O)(O)O)CC#C)/C=C/C3=CC(=CC=C3)OC
InChI 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

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 A_2A 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 A_2A receptor over the adenosine A₁ receptor, 580-fold higher affinity for the adenosine A_2A receptor over the adenosine A_2B 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]