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Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B.
ChemMedChem. 2020 05 06; 15(9):772-786.C

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 A2A AR: 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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Authors+Show Affiliations

Kuder KJ
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Załuski M
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Schabikowski J
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Latacz G
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Olejarz-Maciej A
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Jaśko P
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Doroz-Płonka A
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Brockmann A
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Müller CE
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry University of Bonn, An der Immenburg 4, 53121, Bonn, Germany.
Kieć-Kononowicz K
Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.

MeSH

Dose-Response Relationship, DrugHumansMolecular Docking SimulationMolecular StructureMonoamine OxidaseMonoamine Oxidase InhibitorsNeuroprotective AgentsReceptor, Adenosine A2AStructure-Activity RelationshipXanthines

Pub Type(s)

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

Language

eng

PubMed ID

32162782

Citation

Kuder, Kamil J., et al. "Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting On Adenosine Receptors and Monoamine Oxidase B." ChemMedChem, vol. 15, no. 9, 2020, pp. 772-786.
Kuder KJ, Załuski M, Schabikowski J, et al. Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B. ChemMedChem. 2020;15(9):772-786.
Kuder, K. J., Załuski, M., Schabikowski, J., Latacz, G., Olejarz-Maciej, A., Jaśko, P., Doroz-Płonka, A., Brockmann, A., Müller, C. E., & Kieć-Kononowicz, K. (2020). Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B. ChemMedChem, 15(9), 772-786. https://doi.org/10.1002/cmdc.201900717
Kuder KJ, et al. Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting On Adenosine Receptors and Monoamine Oxidase B. ChemMedChem. 2020 05 6;15(9):772-786. PubMed PMID: 32162782.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B. AU - Kuder,Kamil J, AU - Załuski,Michał, AU - Schabikowski,Jakub, AU - Latacz,Gniewomir, AU - Olejarz-Maciej,Agnieszka, AU - Jaśko,Piotr, AU - Doroz-Płonka,Agata, AU - Brockmann,Andreas, AU - Müller,Christa E, AU - Kieć-Kononowicz,Katarzyna, Y1 - 2020/04/06/ PY - 2019/12/20/received PY - 2020/03/04/revised PY - 2020/3/13/pubmed PY - 2021/5/21/medline PY - 2020/3/13/entrez KW - adenosine receptors KW - dual target ligands KW - molecular docking KW - monoamine oxidase B SP - 772 EP - 786 JF - ChemMedChem JO - ChemMedChem VL - 15 IS - 9 N2 - 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 A2A AR: 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. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/32162782/Novel_Dual_Target_Directed_Annelated_Xanthine_Derivatives_Acting_on_Adenosine_Receptors_and_Monoamine_Oxidase_B_ DB - PRIME DP - Unbound Medicine ER -