TY - JOUR T1 - Pharmacological Characterization of a Novel, Potent Adenosine A<sub>1</sub> and A<sub>2A</sub> Receptor Dual Antagonist, 5-[5-Amino-3-(4-fluorophenyl)pyrazin-2-yl]-1-isopropylpyridine-2(1<em>H</em>)-one (ASP5854), in Models of Parkinson's Disease and Cognition JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 708 LP - 719 DO - 10.1124/jpet.107.121962 VL - 323 IS - 2 AU - Takuma Mihara AU - Kayoko Mihara AU - Junko Yarimizu AU - Yasuyuki Mitani AU - Ritsuko Matsuda AU - Hiroko Yamamoto AU - Satoshi Aoki AU - Atsushi Akahane AU - Akinori Iwashita AU - Nobuya Matsuoka Y1 - 2007/11/01 UR - http://jpet.aspetjournals.org/content/323/2/708.abstract N2 - Central adenosine A2A receptor is a promising target for drugs to treat Parkinson's disease (PD), and the central blockade of adenosine A1 receptor improves cognitive function. In the present study, we investigated the effect of a novel adenosine A1 and A2A dual antagonist, 5-[5-amino-3-(4-fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854), in animal models of PD and cognition. The binding affinities of ASP5854 for human A1 and A2A receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A1 and A2A agonist-induced increases of intracellular Ca2+ concentration. ASP5854 ameliorated A2A 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 A2A antagonist 8-((E)-2-(3,4-dimethoxyphenyl)ethenyl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-purine-2,6-dione (KW-6002; istradefylline) did not. Scopolamine- or 5H-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 A1 and A2A receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A2A antagonism, and also enhances cognitive function through A1 antagonism. The American Society for Pharmacology and Experimental Therapeutics ER -