Pharmacological Characterization of a Novel, Potent Adenosine A1 and A2A Receptor Dual Antagonist, 5-[5-Amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in Models of Parkinson's Disease and Cognition

Central adenosine A 2A receptor is a promising target for drugs to treat Parkinson9s disease (PD), and the central blockade of adenosine A 1 receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A 1 and A 2A dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1 H )-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A 1 and A 2A receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A 1 and A 2A agonist-induced increases of intracellular Ca 2+ concentration. ASP5854 ameliorated A 2A agonist 2-[ p -(2-carboxyethyl) phenethylamino]-5′- N -ethylcarboxamidoadenosine (CGS21680)- and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and it also improved haloperidol-induced catalepsy in rats at doses higher than 0.1 mg/kg. In unilateral 6-hydroxydopamine-lesioned rats, ASP5854 significantly potentiated l -dihydroxyphenylalanine (l-DOPA)-induced rotational behavior at doses higher than 0.032 mg/kg. ASP5854 also significantly restored the striatal dopamine content reduced by 1-metyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment in mice at doses higher than 0.1 mg/kg. Furthermore, in the rat passive avoidance test, ASP5854 significantly reversed the scopolamine-induced memory deficits, whereas the specific adenosine A 2A antagonist 8-(( E )-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1 H -purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine- or 5 H -dibenzo[ a , d ]cyclohepten-5,10-imine (dizocilpine maleate) (MK-801)-induced impairment of spontaneous alternation in the mouse Y-maze test was ameliorated by ASP5854, whereas KW-6002 did not exert improvement at therapeutically relevant dosages. These results demonstrate that the novel, selective, and orally active dual adenosine A 1 and A 2A receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A 2A antagonism, and also enhances cognitive function through A 1 antagonism.