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

Abstract

Central adenosine A 2A receptor is a promising target for drugs to treat Parkinson's 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(1H)-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 2ϩ concentration. ASP5854 ameliorated A 2A agonist 2-[p-(2-carboxyethyl) phenethylamino]-5Ј-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 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.Adenosine is a ubiquitous neuromodulator in the central nervous system. Its major role in the central nervous system is to modulate neurotransmitter release, the postsynaptic components, and also the nonsynaptic components such as glial cell signaling. Adenosine exerts these diverse physiological actions through activation of specific G protein-coupled receptors termed A 1 , A 2A , A 2B , and A 3 (Fredholm et al., 1994).Adenosine A 2A receptors are specifically localized in the striatum (Svenningsson et al., 1999), where they are coexpressed with dopamine D 2 receptors in the GABAergic striaArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.121962. ABBREVIATIONS:CGS21680, 2-[p-(2-carboxyethyl)phenethylamino]-5Ј-N-ethylcarboxamidoadenosine; NECA, N-ethylcarboxamidoadenosine; KW-6002, 7-methyl-3,7-dihydro-1H-purine-2,6-dion...

Brain Adenosine A2A Receptor Occupancy by a Novel A1/A2A Receptor Antagonist, ASP5854, in Rhesus Monkeys: Relationship to Anticataleptic Effect

“…The incidence and duration of cataleptic posture produced by haloperidol injection was reduced by treatment of ASP5854 dose-dependently, a treatment result consistent with our previous observations in rodents. The antimotor-impairment effect of ASP5854 was induced by a dose of from 0.066 to 1 mg/kg, an ED 50 value in various rodent motor-impairment models (13). In the present study with monkeys, the ED 50 value was 0.1 mg/kg, suggesting that the effect of ASP5854 did not have significantly different results among species.…”

“…ASP5854 has potent binding affinities for human adenosine A 1 and A 2A receptors without other molecular targets in the central nervous system (CNS) (13). This compound shows not only improvement of motor impairment in rodent models of PD but also neuroprotective effect on dopaminergic neuronal cell death by specific toxins and antidementia effects in animal models of cognition.…”

“…ASP5854 inhibited haloperidolinduced catalepsy in rodents, induced an increase in the contralateral turning behavior caused by a subthreshold dose of L-3,4-dihydroxyphenylalanine in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway (13), and improved motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated marmosets (Takuma Mihara, unpublished data, 2008). These effects of ASP5854 include the antagonism for adenosine A 2A Rs.…”

“…We have recently identified 5-[5-amino-3-(4fluorophenyl) pyrazin-2-yl]-1-isopropylpyridine-2(1H)-one (ASP5854) as a novel and potent, centrally active adenosine A 1 and A 2A dual antagonist from our optimization screening of pyrazolopyrimidin derivatives (13). ASP5854 inhibited haloperidolinduced catalepsy in rodents, induced an increase in the contralateral turning behavior caused by a subthreshold dose of L-3,4-dihydroxyphenylalanine in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal pathway (13), and improved motor impairment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated marmosets (Takuma Mihara, unpublished data, 2008).…”

Caffeine and Adenosine

“…Independently of the processes used by caffeine or theophylline to improve cognition, there is a consensus that the beneficial effects most of us feel after a few cups of coffee or tea are due to the actions of these psychoactive substances upon ARs. Recent evidence that blockade of A1 receptors improves cognition came from a study using a mixed A1/A2A receptor antagonist, ASP5854 [51]. This orally active drug could reverse scopolamine-induced memory deficits in rats, whereas a specific adenosine A2A AR antagonist, KW-6002, did not.…”