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High-throughput screening and radioligand binding studies reveal monoamine oxidase-B as the primary binding target for D-deprenyl
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC.
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2016 (English)In: Life Sciences, ISSN 0024-3205, E-ISSN 1879-0631, Vol. 152, 231-237 p.Article in journal (Refereed) Published
Abstract [en]

Aims: D-deprenyl is a useful positron emission tomography tracer for visualization of inflammatory processes. Studies with [C-11]-D-deprenyl showed robust uptake in peripheral painful sites of patients with rheumatoid arthritis or chronic whiplash injury. The mechanism of preferential D-deprenyl uptake is not yet known, but the existence of a specific binding site was proposed. Thus, in the present study, we sought to identify the binding site for D-deprenyl and verify the hypothesis about the possibility of monoamine oxidase enzymes as major targets for this molecule. Main methods: A high-throughput analysis of D-deprenyl activity towards 165 G-protein coupled receptors and 84 enzyme targets was performed. Additionally, binding studies were used to verify the competition of [H-3]D-deprenyl with ligands specific for targets identified in the high-throughput screen. Key findings: Our high-throughput investigation identified monoamine oxidase-B, monoamine oxidase-A and angiotensin converting enzyme as potential targets for D-deprenyl. Further competitive [3H] D-deprenyl binding studies with specific inhibitors identified monoamine oxidase-B as the major binding site. No evident high-affinity hits were identified among G-protein coupled receptors. Significance: Our study was the first to utilize a high-throughput screening approach to identify putative D-deprenyl targets. It verified 249 candidate proteins and confirmed the role of monoamine oxidase - B in D-deprenyl binding. Our results add knowledge about the possible mechanism of D-deprenyl binding, which might aid in explaining the increased uptake of this compound in peripheral inflammation. Monoamine oxidase-B will be further investigated in future studies utilizing human inflamed synovium.

Place, publisher, year, edition, pages
2016. Vol. 152, 231-237 p.
Keyword [en]
D-deprenyl High-throughput screening Binding site
National Category
Pharmaceutical Sciences Clinical Medicine
Identifiers
URN: urn:nbn:se:uu:diva-291492DOI: 10.1016/j.lfs.2016.03.058ISI: 000375728500028PubMedID: 27058977OAI: oai:DiVA.org:uu-291492DiVA: diva2:925668
Funder
Berzelii Centre EXSELENT, 2013-01495
Available from: 2016-05-03 Created: 2016-05-03 Last updated: 2016-06-30Bibliographically approved

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Lesniak, AnnaAarnio, MikkoNorberg, ThomasNyberg, FredGordh, Torsten
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Department of Pharmaceutical BiosciencesAnaesthesiology and Intensive CareDepartment of Chemistry - BMC
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