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

Abstract

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 (A1 and A2A 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 A1 receptor over the A2A 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 A1 receptors with a Ki value of 0.369 μM. This compound is reported to also inhibit MAO-B with an IC50 value of 0.020 μM. Such dual-target-directed compounds may act synergistic in the treatment of Parkinson's disease: antagonism of the A1 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 A1 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.

• Authors: Mietha M Van der Walt, Gisella Terre'Blanche, Anél Petzer, Jacobus P Petzer
• Journal: Bioorganic chemistry (Bioorg Chem) Vol. 59 Pg. 117-23 (Apr 2015) ISSN: 1090-2120 [Electronic] United States
• PMID: 25746740 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Monoamine Oxidase Inhibitors
• Phthalimides
• Purinergic P1 Receptor Antagonists
• Receptors, Purinergic P1
• phthalimide
• Monoamine Oxidase

Topics

• Alzheimer Disease (drug therapy, metabolism)
• Humans
• Models, Molecular
• Monoamine Oxidase (metabolism)
• Monoamine Oxidase Inhibitors (chemistry, pharmacology)
• Parkinson Disease (drug therapy, metabolism)
• Phthalimides (chemistry, pharmacology)
• Purinergic P1 Receptor Antagonists (chemistry, pharmacology)
• Receptors, Purinergic P1 (metabolism)
• Structure-Activity Relationship