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Preladenant, a selective A2A receptor antagonist, is active in primate models of movement disorders

2010; Elsevier BV; Volume: 225; Issue: 2 Linguagem: Inglês

10.1016/j.expneurol.2010.07.011

1090-2430

Robert A. Hodgson, Paul J. Bédard, Geoffrey B. Varty, Tatiana M. Kazdoba, Thérèse Di Paolo, Michael E. Grzelak, Annamarie J. Pond, Abdallah Hadj-Tahar, Nancy Bélanger, Laurent Grégoire, Aurelie Dare, Bernard R. Neustadt, Andrew W. Stamford, John C. Hunter,

Receptor Mechanisms and Signaling

Parkinson's Disease (PD) and Extrapyramidal Syndrome (EPS) are movement disorders that result from degeneration of the dopaminergic input to the striatum and chronic inhibition of striatal dopamine D2 receptors by antipsychotics, respectively. Adenosine A2A receptors are selectively localized in the basal ganglia, primarily in the striatopallidal ("indirect") pathway, where they appear to operate in concert with D2 receptors and have been suggested to drive striatopallidal output balance. In cases of dopaminergic hypofunction, A2A receptor activation contributes to the overdrive of the indirect pathway. A2A receptor antagonists, therefore, have the potential to restore this inhibitor imbalance. Consequently, A2A receptor antagonists have therapeutic potential in diseases of dopaminergic hypofunction such as PD and EPS. Targeting the A2A receptor may also be a way to avoid the issues associated with direct dopamine agonists. Recently, preladenant was identified as a potent and highly selective A2A receptor antagonist, and has produced a significant improvement in motor function in rodent models of PD. Here we investigate the effects of preladenant in two primate movement disorder models. In MPTP-treated cynomolgus monkeys, preladenant (1 or 3 mg/kg; PO) improved motor ability and did not evoke any dopaminergic-mediated dyskinetic or motor complications. In Cebus apella monkeys with a history of chronic haloperidol treatment, preladenant (0.3–3.0 mg/kg; PO) delayed the onset of EPS symptoms evoked by an acute haloperidol challenge. Collectively, these data support the use of preladenant for the treatment of PD and antipsychotic-induced movement disorders.