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 A2A receptors in striatum are selectively localized to GABAergic output neurons of the striato-pallidal pathway and may avoid such problems. The novel adenosine A2A 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 A2A receptor antagonists represent a new class of antiparkinsonian agents that improve disability without producing hyperactivity and without inducing dyskinesia.
Kanda
T
T
Neurodegenerative Disease Research Centre, Biomedical Sciences Division, King's College London, UK.
Jackson
M J
MJ
Smith
L A
LA
Pearce
R K
RK
Nakamura
J
J
Kase
H
H
Kuwana
Y
Y
Jenner
P
P
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000704:Analysis of Variance; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001545:Benserazide / Q000627:therapeutic use; D002144:Callithrix; D005260:Female; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines / Q000627:therapeutic use*; D043705:Receptor, Adenosine A2A; D013239:Stereotyped Behavior / Q000187:drug effects; D013997:Time Factors
D000978:Antiparkinson Agents; D058915:Purinergic P1 Receptor Antagonists; D011687:Purines; D043705:Receptor, Adenosine A2A; C111599:istradefylline; D001545:Benserazide; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine