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NEUROPHARMACOLOGY

Pharmacological Characterization of a Novel, Potent Adenosine A₁ and A_2A 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

Pharmacology Research Laboratories (T.M., K.M., J.Y., Y.M., R.M., H.Y., A.I., N.M.) and Chemistry Research Laboratories (S.A., A.A.), Astellas Pharma Inc., Ibaraki, Japan

Central adenosine A_2A 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 A_2A 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 A_2A receptors were 9.03 and 1.76 nM, respectively, with higher specificity and no species differences. ASP5854 also showed antagonistic action on A₁ and A_2A agonist-induced increases of intracellular Ca²⁺ 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-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 A_2A receptors antagonist ASP5854 improves motor impairments, is neuroprotective via A_2A antagonism, and also enhances cognitive function through A₁ antagonism.

Address correspondence to: Dr. Takuma Mihara, Neuroscience Discovery Research, Pharmacology Research Laboratories, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. E-mail: takuma.mihara{at}jp.astellas.com