MSX-3 is a selective

adenosine 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 buildin ...

A_2A receptor antagonist used in

scientific research The scientific method is an empirical method for acquiring knowledge that has characterized the development of science since at least the 17th century (with notable practitioners in previous centuries; see the article history of scientific ...

. Similarly to

MSX-4 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 dopamin ...

, it is a

water-soluble In chemistry, solubility is the ability of a substance Substance may refer to: * Matter, anything that has mass and takes up space Chemistry * Chemical substance, a material with a definite chemical composition * Drug substance ** Substan ...

ester In chemistry, an ester is a compound derived from an oxoacid (organic or inorganic) in which at least one hydroxyl group () is replaced by an alkoxy group (), as in the substitution reaction of a carboxylic acid and an alcohol. Glycerides ...

prodrug of

MSX-2 MSX-2 is a selective adenosine A2A receptor antagonist used in scientific research. It is a xanthine and a derivative of the non-selective adenosine receptor antagonist caffeine. The affinities (Ki) of MSX-2 for the human adenosine receptor ...

Medicinal chemistry

MSX-3, MSX-4, and MSX-2 are

xanthine Xanthine ( or ; archaically xanthic acid; systematic name 3,7-dihydropurine-2,6-dione) is a purine base found in most human body tissues and fluids, as well as in other organisms. Several stimulants are derived from xanthine, including caffeine, ...

s and are

derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. ...

s of the

non-selective In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. The etymology stems from ''ligare'', which means 'to bind'. In protein-ligand binding, the ligand is usually a mol ...

adenosine receptor antagonist 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 (natural: caffeine, theophylline, and theobromine; and synthetic: PSB-1901), but t ...

caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...

. MSX-2 has been extensively studied due to its high

affinity Affinity may refer to: Commerce, finance and law * Affinity (law), kinship by marriage * Affinity analysis, a market research and business management technique * Affinity Credit Union, a Saskatchewan-based credit union * Affinity Equity Part ...

and

selectivity Selectivity may refer to: Psychology and behaviour * Choice, making a selection among options * Discrimination, the ability to recognize differences * Socioemotional selectivity theory, in social psychology Engineering * Selectivity (radio), a ...

for the adenosine A_2A receptor, but use of MSX-2 itself has been limited by its poor water solubility. Whereas MSX-3 is a

phosphate In chemistry, a phosphate is an anion, salt, functional group or ester derived from a phosphoric acid. It most commonly means orthophosphate, a derivative of orthophosphoric acid . The phosphate or orthophosphate ion is derived from phosph ...

ester prodrug of MSX-2 that is suited best for

intravenous administration Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

and not for

oral administration Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are in ...

, MSX-4 is an

amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...

ester ( L-valine) prodrug of MSX-2 that can be orally administered.

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. MSX-3 itself also showed some affinity for the

adenosine receptor 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 dif ...

s, but this may have just been due to

degradation Degradation may refer to: Science * Degradation (geology), lowering of a fluvial surface by erosion * Degradation (telecommunications), of an electronic signal * Biodegradation of organic substances by living organisms * Environmental degradatio ...

phosphatase In biochemistry, a phosphatase is an enzyme that uses water to cleave a phosphoric acid monoester into a phosphate ion and an alcohol. Because a phosphatase enzyme catalyzes the hydrolysis of its substrate, it is a subcategory of hydrolases. Ph ...

s in the ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology and ...

'' system.

Animal studies

MSX-3 shows pro-motivational effects in animals. Specifically, although it showed no effect on its own, the drug reverses the effort-related deficits induced by the

dopamine depleting agent Monoamine-depleting agents are a group of drugs which reversibly deplete one or more monoamine neurotransmitters. One mechanism by which these agents act is by inhibiting reuptake by the vesicular monoamine transporters, VMAT1 and VMAT2. Examples ...

tetrabenazine Tetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorders. It is sold under the brand names Nitoman and Xenazine among others. On August 15, 2008, the U.S. Food and Drug Administration approved the use of tetrabena ...

(TBZ), the

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 8 ...

D₂ receptor antagonists

haloperidol Haloperidol, sold under the brand name Haldol among others, is a typical antipsychotic medication. Haloperidol is used in the treatment of schizophrenia, tics in Tourette syndrome, mania in bipolar disorder, delirium, agitation, acute psychos ...

and

eticlopride Eticlopride is a selective dopamine antagonist A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics ...

, and the

proinflammatory cytokine An inflammatory cytokine or proinflammatory cytokine is a type of signaling molecule (a cytokine) that is secreted from immune cells like helper T cells (Th) and macrophages, and certain other cell types that promote inflammation. They include inte ...

interleukin-6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Sm ...

and interleukin-1β. Conversely, it only mildly attenuates the motivational deficits induced by the dopamine D₁ receptor antagonist

ecopipam Ecopipam (development codes SCH-39166, EBS-101, and PSYRX-101) is a dopamine antagonist which is under development for the treatment of Lesch-Nyhan syndrome, Tourette's syndrome, speech disorders, and restless legs syndrome. It is taken by ...

(SCH-39166).

History

MSX-3 was first described in the

scientific literature : ''For a broader class of literature, see Academic publishing.'' Scientific literature comprises scholarly publications that report original empirical and theoretical work in the natural and social sciences. Within an academic field, sci ...

by 1998. A similar agent, MSX-4, was subsequently described by 2008.

References

{{Purine receptor modulators Adenosine receptor antagonists Experimental drugs Phosphate esters Pro-motivational agents Prodrugs Xanthines Propargyl compounds 3-Methoxyphenyl compounds