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Anti-parkinsonian activity of the adenosine A 2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

KW-6356 is a novel adenosine A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A receptor but also inhibits the constitutive activity of adenosine A receptor. The efficacy of KW-6356 as both monotherapy and an adjunct therapy to L-3,4-dihydroxyphenylalanine...

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Published in:European journal of pharmacology 2023-07, Vol.950, p.175773
Main Authors: Ohno, Yutaro, Okita, Eri, Kawai-Uchida, Mika, Fukuda, Naoko, Shoukei, Youji, Soshiroda, Kazuhiro, Yamada, Koji, Kanda, Tomoyuki, Uchida, Shinichi
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Language:English
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Summary:KW-6356 is a novel adenosine A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A receptor but also inhibits the constitutive activity of adenosine A receptor. The efficacy of KW-6356 as both monotherapy and an adjunct therapy to L-3,4-dihydroxyphenylalanine (L-DOPA)/decarboxylase inhibitor in Parkinson's disease (PD) patients has been reported. However, the first-generation A antagonist istradefylline, which is approved for use as an adjunct treatment to L-DOPA/decarboxylase inhibitor in adult PD patients experiencing OFF episodes, has not shown statistically significant efficacy as monotherapy. In vitro pharmacological studies have shown that the pharmacological properties of KW-6356 and istradefylline at adenosine A receptor are markedly different. However, the anti-parkinsonian activity and effects on dyskinesia of KW-6356 in PD animal models and the differences in the efficacy between KW-6356 and istradefylline are unknown. The present study investigated the anti-parkinsonian activity of KW-6356 as monotherapy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets, and its efficacy was directly compared with that of istradefylline. In addition, we investigated whether or not repeated administration of KW-6356 induced dyskinesia. Oral administration of KW-6356 reversed motor disability in a dose-dependent manner up to 1 mg/kg in MPTP-treated common marmosets. The magnitude of anti-parkinsonian activity induced by KW-6356 was significantly greater than that of istradefylline. Repeated administration of KW-6356 induced little dyskinesia in MPTP-treated common marmosets primed to exhibit dyskinesia by prior exposure to L-DOPA. These results indicate that KW-6356 can be a novel non-dopaminergic therapy as monotherapy without inducing dyskinesia in PD patients.
ISSN:1879-0712
DOI:10.1016/j.ejphar.2023.175773