MSX-2

Last updated
MSX-2
MSX-2.svg
Clinical data
Other names3-(3-Hydroxypropyl)-7-methyl-8-(3-methoxystyryl)-1-propargylxanthine
Drug class Adenosine A2A receptor antagonist
Identifiers
  • 3-(3-hydroxypropyl)-8-[(E)-2-(3-methoxyphenyl)ethenyl]-7-methyl-1-prop-2-ynylpurine-2,6-dione
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
ChEMBL
CompTox Dashboard (EPA)
Chemical and physical data
Formula C21H22N4O4
Molar mass 394.431 g·mol−1
3D model (JSmol)
  • CN1C(=NC2=C1C(=O)N(C(=O)N2CCCO)CC#C)/C=C/C3=CC(=CC=C3)OC
  • 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 A2A 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 (Ki) of MSX-2 for the human adenosine receptors are 5.38 to 14.5 nM for the adenosine A2A receptor, 2,500 nM for the adenosine A1 receptor (172- to 465-fold lower than for the A2A receptor), and >10,000 nM for the adenosine A2B and A3 receptors (>690-fold lower than for the A2A 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]

See also

Related Research Articles

<span class="mw-page-title-main">Adenosine</span> Chemical compound

Adenosine (symbol A) is an organic compound that occurs widely in nature in the form of diverse derivatives. The molecule consists of an adenine attached to a ribose via a β-N9-glycosidic bond. Adenosine is one of the four nucleoside building blocks of RNA (and its derivative deoxyadenosine is a building block of DNA), which are essential for all life on Earth. Its derivatives include the energy carriers adenosine mono-, di-, and triphosphate, also known as AMP/ADP/ATP. Cyclic adenosine monophosphate (cAMP) is pervasive in signal transduction. Adenosine is used as an intravenous medication for some cardiac arrhythmias.

<span class="mw-page-title-main">Adenosine receptor</span> Class of four receptor proteins to the molecule adenosine

The adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B and A3; each is encoded by a different gene.

Adenosine A<sub>2A</sub> receptor Cell surface receptor found in humans

The adenosine A2A receptor, also known as ADORA2A, is an adenosine receptor, and also denotes the human gene encoding it.

<span class="mw-page-title-main">SCH-58261</span> Chemical compound

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<span class="mw-page-title-main">Istradefylline</span> Chemical compound

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<span class="mw-page-title-main">ZM-241,385</span> Chemical compound

ZM-241,385 is a high affinity antagonist ligand selective for the adenosine A2A receptor.

<span class="mw-page-title-main">PSB-10</span> Chemical compound

PSB-10 is a drug which acts as a selective antagonist for the adenosine A3 receptor (ki value at human A3 receptor is 0.44 nM), with high selectivity over the other three adenosine receptor subtypes (ki values at human A1, A2A and A2B receptors are 4.1, 3.3 and 30 μM). Further pharmacological experiments in a [35S]GTPγS binding assay using hA3-CHO-cells indicated that PSB-10 acts as an inverse agonist (IC50 = 4 nM). It has been shown to produce antiinflammatory effects in animal studies. Simple xanthine derivatives such as caffeine and DPCPX have generally low affinity for the A3 subtype and must be extended by expanding the ring system and adding an aromatic group to give high A3 affinity and selectivity. The affinity towards adenosine A3 subtype was measured against the radioligand PSB-11.

<span class="mw-page-title-main">Preladenant</span> Chemical compound

Preladenant is a drug that was developed by Schering-Plough which acted as a potent and selective antagonist of the adenosine A2A receptor. It was being researched as a potential treatment for Parkinson's disease. Positive results were reported in Phase II clinical trials in humans, but it did not prove itself to be more effective than a placebo during Phase III trials, and so was discontinued in May 2013.

<span class="mw-page-title-main">CGS-15943</span> Chemical compound

CGS-15943 is a drug which acts as a potent and reasonably selective antagonist for the adenosine receptors A1 and A2A, having a Ki of 3.3nM at A2A and 21nM at A1. It was one of the first adenosine receptor antagonists discovered that is not a xanthine derivative, instead being a triazoloquinazoline. Consequently, CGS-15943 has the advantage over most xanthine derivatives that it is not a phosphodiesterase inhibitor, and so has more a specific pharmacological effects profile. It produces similar effects to caffeine in animal studies, though with higher potency.

<span class="mw-page-title-main">8-Cyclopentyl-1,3-dimethylxanthine</span> Chemical compound

8-Cyclopentyl-1,3-dimethylxanthine (8-Cyclopentyltheophylline, 8-CPT, CPX) is a drug which acts as a potent and selective antagonist for the adenosine receptors, with some selectivity for the A1 receptor subtype, as well as a non-selective phosphodiesterase inhibitor. It has stimulant effects in animals with slightly higher potency than caffeine.

<span class="mw-page-title-main">ATL-444</span> Chemical compound

ATL-444 is a drug which acts as a potent and reasonably selective antagonist for the adenosine receptors A1 and A2A. It has been used to study the role of the adenosine receptor system in the reinforcing action of cocaine, as well as the development of some cancers.

An adenosine receptor antagonist is a drug which acts as an antagonist of one or more of the adenosine receptors. The best known are xanthines and their derivatives, but there are also non-xanthine representatives

Adenosine A2A receptor antagonists are a class of drugs that blocks adenosine at the adenosine A2A receptor. Notable adenosine A2A receptor antagonists include caffeine, theophylline and istradefylline.

<span class="mw-page-title-main">Monoamine-depleting agent</span> Drug class

Monoamine-depleting agents are a group of drugs which reversibly deplete one or more of the monoamine neurotransmitters, serotonin, dopamine, and norepinephrine. One mechanism by which these agents act is by inhibiting reuptake by the vesicular monoamine transporters, VMAT1 and VMAT2. Examples of monoamine-depleting agents include deutetrabenazine, oxypertine, reserpine, tetrabenazine, and valbenazine. Tetrabenazine selectively depletes dopamine at low doses and is used as an animal model of amotivation.

<span class="mw-page-title-main">Motivation-enhancing drug</span> Drug increasing motivation in humans

A motivation-enhancing drug, also known as a pro-motivational drug, is a drug which increases motivation. Drugs enhancing motivation can be used in the treatment of motivational deficits, for instance in depression, schizophrenia, and attention deficit hyperactivity disorder (ADHD). They can also be used in the treatment of disorders of diminished motivation (DDMs), including apathy, abulia, and akinetic mutism, disorders that can be caused by conditions like stroke, traumatic brain injury (TBI), and neurodegenerative diseases. Motivation-enhancing drugs are used non-medically by healthy people to increase motivation and productivity as well, for instance in educational contexts.

<span class="mw-page-title-main">Lu AA47070</span> An adenosine A2A receptor antagonist for Parkinsons disease that was abandoned

Lu AA47070 is a selective adenosine A2A receptor antagonist that was under development for the treatment of Parkinson's disease but was never marketed. It has been found to reverse some of the effects of dopamine D2 receptor antagonists like pimozide and haloperidol, for instance tremulous jaw movements, catalepsy, locomotor suppression, and other anti-motivational effects, in animals. The drug is a prodrug of Lu AA41063. It was discontinued in phase 1 clinical trials because it lacked the intended pharmacological properties in humans. Lu AA47070 was first described by 2008.

<span class="mw-page-title-main">MSX-3</span> Selective adenosine A2A receptor antagonist used in scientific research

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.

<span class="mw-page-title-main">3-Chlorostyrylcaffeine</span> A selective adenosine A2A receptor antagonist and MAO-B inhibitor used in scientific research

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<span class="mw-page-title-main">MSX-4</span> Selective adenosine A2A receptor antagonist

MSX-4 is a selective adenosine A2A receptor antagonist used in scientific research. It is a water-soluble amino acid ester prodrug of MSX-2, the active metabolite of the drug. MSX-4 reverses the motivational deficits induced by the dopamine D2 receptor antagonist eticlopride in animals and hence has the capacity to produce pro-motivational effects. MSX-4 was first described in the scientific literature by 2008.

<span class="mw-page-title-main">Lu AA41063</span> A selective adenosine A2A receptor antagonist

Lu AA41063 is a selective adenosine A2A receptor antagonist. Structurally, it is a non-xanthine.

References

  1. 1 2 3 4 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.
  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.
  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.
  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.
  5. 1 2 3 4 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.
  6. 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.
  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.
  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.
  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.
  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.
  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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