Received for publication February 26, 2007.
Revised August 3, 2007.
Accepted for publication August 6, 2007.

Pharmacological characterization of a novel, potent adenosine A₁ and A_2A receptor dual antagonist, ASP5854, in models of Parkinson's disease and cognition

Abstract

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-(4fluorophenyl) 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 (CGS21680)- and haloperidol-induced catalepsy in mice, with the minimum effective doses of 0.32 and 0.1 mg/kg, respectively, and 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 (MPTP) 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, KW-6002 (istradefylline), did not. Scopolamine- or MK-801-induced impairment of spontaneous alternation in the mouse Y-maze test were 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.

Key words: ASP5854, Adenosine, KW-6002, Parkinson's disease, cognition, dopamine

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