The novel adenosine A2a 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-(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.

• Authors: Sarah Rose, Michael J Jackson, Lance A Smith, Kim Stockwell, Louisa Johnson, Paolo Carminati, Peter Jenner
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 546 Issue 1-3 Pg. 82-7 (Sep 28 2006) ISSN: 0014-2999 [Print] Netherlands
• PMID: 16925991 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-n-butyl-9-methyl-8-(1,2,3)triazol-2-yl-9H-purin-6-ylamine
• Adenosine A2 Receptor Antagonists
• Antiparkinson Agents
• Triazoles
• Levodopa
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology, therapeutic use)
• Adenosine A2 Receptor Antagonists
• Animals
• Antiparkinson Agents (pharmacology, therapeutic use)
• Callithrix
• Dose-Response Relationship, Drug
• Drug Synergism
• Drug Therapy, Combination
• Dyskinesia, Drug-Induced (drug therapy, physiopathology)
• Female
• Levodopa (pharmacology, therapeutic use)
• MPTP Poisoning (drug therapy, physiopathology)
• Male
• Motor Activity (drug effects)
• Motor Skills (drug effects)
• Triazoles (pharmacology, therapeutic use)