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Parkinson’s disease (PD) represents the second most common neurodegenerative disorder worldwide. So far, available treat- ments possess mere symptomatic action and severe long-term side effects, so the development of neuroprotective strategies is highly needed. It is now widely recognized that neuroinflammation is crucial in PD, especially in the disease progression. Therefore, pharmacological treatments able to modulate the pathological immune response may reveal effective in slowing disease progression. The microglial cells are the key component of the brain immune system and can be activated by adenosine through the interaction with A2AARs (A2A adenosine receptors). Indeed, the modulation of purinergic receptors has been associated with a slower degeneration of nigrostriatal dopaminergic cells in PD. Since previous findings demonstrating the ability of A2AAR antagonist 8-ethoxy-9-ethyladenine (ANR94) to protect nigrostriatal neurons from neuroinflammation in an animal model of PD (1), several ad hoc-designed A2AAR antagonists (ANR94 ana- logues) have been synthetized and tested in activated BV-2 microglial cells. To mimic neuroinflammation BV-2 cells were exposed to 100 ng/mL LPS or 0.5 mM MPP+ for 24 h. The potential anti-inflammatory activity of ANR94 analogues were evaluated by MTT assay and measuring the reactive oxygen spe- cies (ROS) levels by DCF-DA probe, while gene expression anal- yses of inflammatory cytokines such as TNFa, IL-1b and the pro-inflammatory enzymes iNOS and COX-2 were performed by RT-PCR. Interestingly, the newly synthetized compounds were more effective than the lead compound ANR94 in counteracting inflammatory damage suggesting their potential use as therapeu- tic agent to prevent/counteract PD. Of course, animal and clini- cal studies are needed to investigate their in vivo activity. This work was supported by MIUR-PRIN n. 20152HKF3Z and University of Camerino n. FPI000065. 1. Pinna A et al. (2005) Eur J Pharmacol 512, 157–164.

Objectives We investigated the effects of novel selective and non-selective adenosine receptor agonists (ARs) on cardioprotection. Methods Male rabbits divided into six groups were subjected to 30-min heart ischaemia and 3-h reperfusion: (1) control group, (2) postconditioning (PostC) group, (3) group A: treated with the non-selective agonist (S)-PHPNECA, (4) group B: treated with the A1 agonist CCPA, (5) group C: treated with the A2A agonist VT 7 and (6) group D: treated with the A3 agonist AR 170. The infarcted (I) and the areas at risk (R) were estimated as %I/R. In additional rabbits of all groups, heart samples were taken for determination of Akt, eNOS and STAT 3 at the 10th reperfusion minute. Key findings (S)-PHPNECA and CCPA reduced the infarct size (17.2±2.9% and 17.9±2.0% vs 46.8±1.9% in control, P

The A\(_{2A}\) adenosine receptor (A\(_{2A}\)AR) is one of the four subtypes activated by nucleoside adenosine, and the molecules able to selectively counteract its action are attractive tools for neurodegenerative disorders. In order to find novel A\(_{2A}\)AR ligands, two series of compounds based on purine and triazolotriazine scaffolds were synthesized and tested at ARs. Compound 13 was also tested in an in vitro model of neuroinflammation. Some compounds were found to possess high affinity for A\(_{2A}\)AR, and it was observed that compound 13 exerted anti-inflammatory properties in microglial cells. Molecular modeling studies results were in good agreement with the binding affinity data and underlined that triazolotriazine and purine scaffolds are interchangeable only when 5- and 2-positions of the triazolotriazine moiety (corresponding to the purine 2- and 8-positions) are substituted.

Although significant progress has been made in the past few decades demonstrating that adenosine modulates a variety of physiological and pathophysiological processes through the interaction with four subtypes of a family of cell-surface G-protein-coupled receptors, clinical evaluation of some adenosine receptor ligands has been discontinued. Major problems include side effects due to the wide distribution of adenosine receptors, low brain penetration (which is important for the targeting of CNS diseases), short half-life of compounds, or a lack of effects, in some cases perhaps due to receptor desensitization or to low receptor density in the targeted tissue. Currently, three A(2A) adenosine receptor agonists have begun phase III studies. Two of them are therapeutically evaluated as pharmacologic stress agents and the third proved to be effective in the treatment of acute spinal cord injury (SCI), while avoiding the adverse effects of steroid agents. On the other hand, the great interest in the field of A(2A) adenosine receptor antagonists is related to their application in neurodegenerative disorders, in particular, Parkinson's disease, and some of them are currently in various stages of evaluation. This review presents an update of medicinal chemistry and molecular recognition of A(2A) adenosine receptor agonists and antagonists, and stresses the strong need for more selective ligands at the A(2A) human subtype.