Adenosine A2a receptor antagonists

Baraldi, P. G., Cacciari, B., Romagnoli, R., Spalluto, G., Monopoli, A., Ongini, E., Varani, K., Borea, P. A. 7-Substituted 5-amino-2-(2-furyl)pyrazolo[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidines as A2A adenosine receptor antagonists a study on the importance of modifications at the side chain on the activity and solubility, J. Med. Chem. 2002, 45, 115-126. 

Zhang X, Tellew JE, Luo Z, et al. Lead optimization of 4-acetylaniino-2-(3,5-dimethylpyrazol-l-yl)-6-pyridylpyriniidines as A2A adenosine receptor antagonists for the treatment of Parkinson s disease. J Med Chem 2008 51 7099-7110. 

J. Leppanen, J. Huuskonen, J. Savolainen, T. Nevalainen, H. Taipale, J. Vepsalainen, J. Gynther, T. Jarvinen, Synthesis of a Water-Soluble Prodrug of Entacapone , Bioorg. Med. Chem. Lett. 2000, 10, 1967-1969 R. Sauer, J. Maurinsh, U. Reith, F. Ftille, K. N. Klotz, C. E. Muller, Water-Soluble Phosphate Prodrugs of l-Propargyl-8-styryl-xanthine Derivatives, A2A-Selective Adenosine Receptor Antagonists , J. Med. Chem. 2000, 43, 440-448. 

ADENOSINE RECEPTOR ANTAGONIST selective for the A2A-subtype. It is used as a tool in adenosine receptor studies, and is reported to be neuroprotective in animal model of cerebral ischaemia. 

Other mediators have also been related to CsA-in-duced functional nephrotoxicity. Increased plasma level of adenosine due to reduced uptake by red blood cells was observed in CsA-treated renal transplant recipients [183]. In the same way, rats receiving CsA showed increased concentration of adenosine in renal artery paralleled by a decrease in mRNA expression for Aj and A2a renal adenosine receptors [184]. Experimental use of selective Aj adenosine receptors antagonists or theophylline resulted in contradictory results with some authors finding renal hemodynamic and functional protection whereas other did not [38, 185-187]. Moderate increases in plasma vasopressin were observed in CsA-treated renal transplant recipients [188] and CsA enhanced vasopressin-induced rise in intracellular calcium in cultured glomerular mesangial... 

Sleepiness is mediated by adenosine receptors. Caffeine, a well-known stimulant in coffee, tea, and some sodas, prevents adenosine from binding to adenosine receptors. It stimulates wakefulness by its antagonistic effect on A1 and A2a adenosine receptors. 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Adenosine A2a receptors are localized to the indirect striatal output function and control motor behavior. Istradefylline is a novel adenosine A2a receptor antagonist, which demonstrated a clinically meaningful reduction in motor fluctuations in L-DOPA-treated patients with established motor complications, and is safe and well tolerated. 

PI (adenosine) receptors were explored as therapeutic targets before P2 receptors. Adenosine was identified early and is in current use to treat supraventricular tachycardia. A2a receptor antagonists are being investigated for the treatment of Parkinson s disease and patents have been lodged for the application of PI receptor subtype agonists and antagonists for myocardial ischaemia and reperfusion injury, cerebral ischaemia, stroke, intermittent claudication and renal insufficiency. 

Richardson, PJ, Kase, H and Jenner, PG (1997) Adenosine A2A receptor antagonists as new agents for the treatment of Parkinson s disease. Trends Pharmacol. Sci. 18 338-344. 

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