Ken Ikeda

Neuroprotection by adenosine A2A receptor blockade in experimental models of Parkinson's disease

Adenosine A2A receptors are abundant in the caudate‐putamen and involved in the motor control in several species. In MPTP‐treated monkeys, A2A receptor‐blockade with an antagonist alleviates parkinsonian symptoms without provoking dyskinesia, suggesting this receptor may offer a new target for the antisymptomatic therapy of Parkinsons disease. In the present study, a significant neuroprotective effect of A2A receptor antagonists is shown in experimental models of Parkinsons disease. Oral administration of A2A receptor antagonists protected against the loss of nigral dopaminergic neuronal cells induced by 6‐hydroxydopamine in rats. A2A antagonists also prevented the functional loss of dopaminergic nerve terminals in the striatum and the ensuing gliosis caused by MPTP in mice. The neuroprotective property of A2A receptor antagonists may be exerted by altering the packaging of these neurotoxins into vesicles, thus reducing their effective intracellular concentration. We therefore conclude that the adenosine A2A receptor may provide a novel target for the long‐term medication of Parkinsons disease, because blockade of this receptor exerts both acutely antisymptomatic and chronically neuroprotective activities.

Synthetic studies on selective adenosine A2A receptor antagonists. Part II: Synthesis and structure–activity relationships of novel benzofuran derivatives

A series of benzofuran derivatives were prepared to study their antagonistic activities to the A(2A) receptor. Replacement of the ester group of the lead compound 1 with phenyl ring improved the PK profile, while modifications of the amide moiety showed enhanced antagonistic activity. From these studies, compounds 13c, 13f, and 24a showed good potency in vitro and were identified as novel A(2A) receptor antagonists suitable for oral activity evaluation in animal models of catalepsy.