The novel adenosine A 2a receptor antagonist ST1535 potentiates the effects of a threshold dose of l-DOPA in MPTP treated common marmosets

Abstract

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-(2 H-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.