An Update on Adenosine A2A Receptors as Drug Target in Parkinson's Disease

Antoni      Vallano; Víctor      Fernandez-Duenas; Consuelo      Pedros; Josep      Maria Arnau; Francisco      Ciruela

doi:10.2174/187152711797247803

Abstract

Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A2A receptors (A2ARs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D2 receptor (D2R). Furthermore, it is assumed that the formation of balanced A2AR/D2R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A2AR activation reduces the affinity of striatal D2R for dopamine and the blockade of A2AR with specific antagonists facilitates function of the D2R. Thus, it may be postulated that A2AR antagonists are pro-dopaminergic agents. Therefore, A2AR antagonists will potentially reduce the effects associated with dopamine depletion in Parkinson's disease (PD). Accordingly, this class of compounds have recently attracted considerable attention as potential therapeutic agents for PD pharmacotherapy as they have shown potential effectiveness in counteracting motor dysfunctions and also displayed neuroprotective and anti-inflammatory effects in animal models of PD. Overall, we provide here an update of the current state of the art of these A2AR-based approaches that are under clinical study as agents devoted to alleviate PD symptoms.

Keywords: Adenosine A2A receptors, Parkinsons disease, GPCR oligmerisation, Clinical trials, Istradefylline, Preladenant, Medium spiny neurons, Bradykinesia, Neuropeptides dynorphin, COMT, SRET, Alzheimers disease, Huntingtons disease, cerebral ischemia