Anti-parkinsonian activity of the adenosine A2A receptor antagonist/inverse agonist KW-6356 as monotherapy in MPTP-treated common marmosets

• Published in: European journal of pharmacology 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
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 05.07.2023
• Subjects: Adenosine A2A receptor; Anti-parkinsonian; Dyskinesia; MPTP-Treated common marmosets; Anti-parkinsonian; MPTP-Treated common marmosets; Adenosine A2A receptor; Dyskinesia
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2023.175773

KW-6356 is a novel adenosine A2A receptor antagonist/inverse agonist that not only blocks binding of adenosine to adenosine A2A receptor but also inhibits the constitutive activity of adenosine A2A 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 A2A 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 A2A 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. •KW-6356 reverses motor disability in untreated parkinsonian common marmosets.•KW-6356 is more effective on motor disability of animal model than istradefylline.•KW-6356 does not induce dyskinesia in L-DOPA-primed parkinsonian common marmosets.