The novel adenosine A2a receptor antagonist ST1535 potentiates the effects of a threshold dose of L-DOPA in MPTP treated common marmosets.
Adenosine A(2a) receptor antagonists may represent a novel non-dopaminergic approach to the treatment of Parkinson's disease. However, there is little information available on their ability to reverse motor deficits in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine hydrochloride (MPTP)-treated primates. We have studied the effects of the novel A(2a) receptor antagonist 2-butyl-9-methyl-8-(2H-1,2,3-triazol 2-yl)-9 H-purin-6-ylamine (ST1535) alone and in combination with l-3, 4-dihydroxyphenylalanine (L-DOPA) in MPTP-treated common marmosets. ST1535 (10, 20 and 40 mg/kg, p.o.) when administered alone to MPTP-treated common marmosets produced a dose related increase in locomotor motor activity and tended to reverse motor disability. Treatment with a threshold dose of L-DOPA (2.5 mg/kg, p.o.) produced an increase in locomotor activity and again tended to reverse motor disability. When L-DOPA (2.5 mg/kg, p.o.) was administered in combination with ST1535 (20 mg/kg, p.o.), there was an enhancement in the intensity and duration of the effect of L-DOPA (2.5 mg/kg, p.o.) in reversing motor deficits as shown by both a further increase in locomotor activity and reversal of motor disability. The combination of L-DOPA (2.5 mg/kg, p.o.) plus ST1535 (20 mg/kg, p.o.) significantly increased "on time" in these animals. These data substantiate the evidence that adenosine A(2a) receptor antagonists are able to reverse motor deficits in a highly predictive model of clinical efficacy in Parkinson's disease. The data suggests that ST1535 will be an effective anti-parkinsonian agent in combination with L-DOPA and allow a reduction in l-DOPA usage in the treatment of Parkinson's disease.
Rose
Sarah
S
Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College, London SE1 1UL UK.
Jackson
Michael J
MJ
Smith
Lance A
LA
Stockwell
Kim
K
Johnson
Louisa
L
Carminati
Paolo
P
Jenner
Peter
P
D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002144:Callithrix; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy / Q000503:physiopathology; D005260:Female; D007980:Levodopa / Q000494:pharmacology* / Q000627:therapeutic use; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009048:Motor Skills / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
C506291:2-n-butyl-9-methyl-8-(1,2,3)triazol-2-yl-9H-purin-6-ylamine; D058917:Adenosine A2 Receptor Antagonists; D000978:Antiparkinson Agents; D014230:Triazoles; D007980:Levodopa; D000225:Adenine