The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues

Based on a report that sulfanylphthalimides are highly potent monoamine oxidase (MAO) B selective inhibitors, the present study examines the adenosine receptor affinities and MAO-B inhibitory properties of a series of 4- and 5-sulfanylphthalimide analogues. Since adenosine antagonists (A(1) and A(2A) subtypes) and MAO-B inhibitors are considered agents for the therapy of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, dual-target-directed drugs that antagonize adenosine receptors and inhibit MAO-B may have enhanced therapeutic value. The results document that the sulfanylphthalimide analogues are selective for the adenosine A(1) receptor over the A(2A) receptor subtype, with a number of compounds also possessing MAO-B inhibitory properties. Among the compounds evaluated, 5-[(4-methoxybenzyl)sulfanyl] phthalimide was found to possess the highest binding affinity to adenosine A(1) receptors with a K-i value of 0.369 mu M. This compound is reported to also inhibit MAO-B with an IC50 value of 0.020 mu M. Such dual-target-directed compounds may act synergistic in the treatment of Parkinson's disease: antagonism of the A(1) receptor may facilitate dopamine release, while MAO-B inhibition may reduce dopamine metabolism. Additionally, dual-target-directed compounds may find therapeutic value in Alzheimer's disease: antagonism of the A(1) receptor may be beneficial in the treatment of cognitive dysfunction, while MAO-B inhibition may exhibit neuroprotective properties. In neurological diseases, such as Parkinson's disease and Alzheimer's disease, dual-target-directed drugs are expected to be advantageous over single-target treatments. (C) 2015 Elsevier Inc. All rights reserved.