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 (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.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: 13035134@nwu.ac.za.
Mietha M
MM
Van der Walt
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Gisella
G
Terre'Blanche
Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Anél
A
Petzer
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Jacobus P
JP
Petzer
D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism; D010797:Phthalimides / Q000737:chemistry* / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D010797:Phthalimides; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; C037431:phthalimide; D008995:Monoamine Oxidase
Adenosine A(1) receptors; Adenosine A(2A) receptors; Alzheimer’s disease; Monoamine oxidase B; Parkinson’s disease; Sulfanylphthalimides