Adenosine A2A Antagonist: A novel antiparkinsonian agent that does not provoke dyskinesia in Parkinsonian monkeys

Abstract

Treatment of Parkinson's disease with L‐dopa therapy leads to long‐term complications, including loss of drug efficacy and the onset of dyskinesia. Adenosine A 2A receptors in striatum are selectively localized to GABAergic output neurons of the striato‐pallidal pathway and may avoid such problems. The novel adenosine A 2A receptor antagonist KW‐6002 has been examined for antiparkinsonian activity in MPTP‐treated primates. Oral administration of KW‐6002 reversed motor disability in MPTP‐treated common marmosets in a dose‐dependent manner. However, KW‐6002 only modestly increased overall locomotor activity and did not cause abnormal movement, such as stereotypy. The ability of KW‐6002 to reverse motor disability was maintained on repeated daily administration for 21 days, and no tolerance was observed. KW‐6002 induced little or no dyskinesia in MPTP‐treated primates previously primed to exhibit dyskinesia by prior exposure to L‐dopa. These results suggest that selective adenosine A 2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.