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8-Benzyltetrahydropyrazino[2,1-f]purinediones: Water-Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases

Authors

  • Dr. Andreas Brunschweiger,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
    2. Faculty for Chemistry and Chemical Biology TU Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund (Germany)
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  • Dr. Pierre Koch,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
    2. Institute of Pharmaceutical Sciences, Faculty of Science Eberhard Karls Universität Tübingen Auf der Morgenstelle 8, 72076 Tübingen (Germany)
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  • Dr. Miriam Schlenk,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Felipe Pineda,

    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Petra Küppers,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Sonja Hinz,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Meryem Köse,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Stefan Ullrich,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Jörg Hockemeyer,

    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Prof. Dr. Michael Wiese,

    1. Pharmaceutical Chemistry II, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
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  • Dr. Jag Heer,

    1. CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A. Chemin du Foriest, 1420 Braine l'Alleud (Belgium)
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  • Prof. Dr. Christa E. Müller

    Corresponding author
    1. Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)
    • Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany)===

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Abstract

8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to improve water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine receptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A1/A2A adenosine receptor antagonists were identified. Several compounds showed triple-target inhibition; one of the best compounds was 8-(2,4-dichloro-5-fluorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (72) (human AR: Ki A1 217 nM, A2A 233 nM; IC50 MAO-B: 508 nM). Dichlorinated compound 36 [8-(3,4-dichlorobenzyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione] was found to be the best triple-target drug in rat (Ki A1 351 nM, A2A 322 nm; IC50 MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that act at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics.

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