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

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-G002 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.