Abstract

The current pharmacological therapies for the treatment of Parkinson’s disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A_2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A_2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D₂ receptors. MAO-B inhibitors are established therapy of Parkinson’s disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A_2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson’s disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A_2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A_2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A_2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson’s disease.

Keywords: Adenosine A_2A receptor, caffeine, drug design, dual-target-directed, inhibition, monoamine oxidase, Parkinson’s disease.