Inhibition of monoamine oxidase B by selective adenosine A2A receptor antagonists

Abstract

Adenosine receptor antagonists that are selective for the A2A receptor subtype (A2A antagonists) are under investigation as possible therapeutic agents for the symptomatic treatment of the motor deficits associated with Parkinson's disease (PD). Results of recent studies in the MPTP mouse model of PD suggest that A2A antagonists may possess neuroprotective properties. Since monoamine oxidase B (MAO-B) inhibitors also enhance motor function and reduce MPTP neurotoxicity, we have examined the MAO-B inhibiting properties of several A2A antagonists and structurally related compounds in an effort to determine if inhibition of MAO-B may contribute to the observed neuroprotection. The results of these studies have established that all of the (E)-8-styrylxanthinyl derived A2A antagonists examined display significant MAO-B inhibitory properties in vitro with Ki values in the low μM to nM range. Included in this series is (E)-1,3-diethyl-8-(3,4-dimethoxystyryl)-7-methylxanthine (KW-6002), a potent A2A antagonist and neuroprotective agent that is in clinical trials. The results of these studies suggest that MAO-B inhibition may contribute to the neuroprotective potential of A2A receptor antagonists such as KW-6002 and open the possibility of designing dual targeting drugs that may have enhanced therapeutic potential in the treatment of PD.