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The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues.
Bioorg Chem. 2015 Apr; 59:117-23.BC

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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Van der Walt MM
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: 13035134@nwu.ac.za.
Terre'Blanche G
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Petzer A
Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Petzer JP
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.

MeSH

Alzheimer DiseaseHumansModels, MolecularMonoamine OxidaseMonoamine Oxidase InhibitorsParkinson DiseasePhthalimidesPurinergic P1 Receptor AntagonistsReceptors, Purinergic P1Structure-Activity Relationship

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25746740

Citation

Van der Walt, Mietha M., et al. "The Adenosine Receptor Affinities and Monoamine Oxidase B Inhibitory Properties of Sulfanylphthalimide Analogues." Bioorganic Chemistry, vol. 59, 2015, pp. 117-23.
Van der Walt MM, Terre'Blanche G, Petzer A, et al. The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues. Bioorg Chem. 2015;59:117-23.
Van der Walt, M. M., Terre'Blanche, G., Petzer, A., & Petzer, J. P. (2015). The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues. Bioorganic Chemistry, 59, 117-23. https://doi.org/10.1016/j.bioorg.2015.02.005
Van der Walt MM, et al. The Adenosine Receptor Affinities and Monoamine Oxidase B Inhibitory Properties of Sulfanylphthalimide Analogues. Bioorg Chem. 2015;59:117-23. PubMed PMID: 25746740.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues. AU - Van der Walt,Mietha M, AU - Terre'Blanche,Gisella, AU - Petzer,Anél, AU - Petzer,Jacobus P, Y1 - 2015/02/18/ PY - 2014/11/17/received PY - 2015/02/09/revised PY - 2015/02/11/accepted PY - 2015/3/10/entrez PY - 2015/3/10/pubmed PY - 2016/1/12/medline KW - Adenosine A(1) receptors KW - Adenosine A(2A) receptors KW - Alzheimer’s disease KW - Monoamine oxidase B KW - Parkinson’s disease KW - Sulfanylphthalimides SP - 117 EP - 23 JF - Bioorganic chemistry JO - Bioorg Chem VL - 59 N2 - 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. SN - 1090-2120 UR - https://www.unboundmedicine.com/medline/citation/25746740/The_adenosine_receptor_affinities_and_monoamine_oxidase_B_inhibitory_properties_of_sulfanylphthalimide_analogues_ DB - PRIME DP - Unbound Medicine ER -