Novel,Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B |
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Authors: | Dr. Kamil J. Kuder Michał Załuski Jakub Schabikowski Dr. Gniewomir Latacz Agnieszka Olejarz-Maciej Piotr Jaśko Agata Doroz-Płonka Andreas Brockmann Prof. Christa E. Müller Prof. Katarzyna Kieć-Kononowicz |
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Affiliation: | 1. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland;2. PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry University of Bonn, An der Immenburg 4, 53121 Bonn, Germany |
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Abstract: | Annelated purinedione derivatives have been shown to act as possible multiple-target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido- and diazepino[2,1-f]purinedione derivatives were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. This allowed 9-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione ( 13 e ; Ki human A2AAR: 264 nM and IC50 human MAO-B: 243 nM) to be identified as the most potent dual-acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure-activity relationships was complemented by molecular-docking studies based on previously published X-ray structures of the protein targets. Such dual-acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO-B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease |
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Keywords: | adenosine receptors dual target ligands monoamine oxidase B molecular docking |
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