title: 8-Benzyltetrahydropyrazino[2,1-f]purinediones: water-soluble tricyclic xanthine derivatives as multitarget drugs for neurodegenerative diseases.
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.
authors.affiliation: Pharmaceutical Chemistry I, Pharmaceutical Institute, PharmaCenter Bonn, University of Bonn, An der Immenburg 4, 53121 Bonn (Germany); Faculty for Chemistry and Chemical Biology TU Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund (Germany).
authors.forename: Andreas
authors.initials: A
authors.lastname: Brunschweiger
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.forename: Miriam
authors.initials: M
authors.lastname: Schlenk
authors.forename: Felipe
authors.initials: F
authors.lastname: Pineda
authors.forename: Petra
authors.initials: P
authors.lastname: Küppers
authors.forename: Sonja
authors.initials: S
authors.lastname: Hinz
authors.forename: Meryem
authors.initials: M
authors.lastname: Köse
authors.forename: Stefan
authors.initials: S
authors.lastname: Ullrich
authors.forename: Jörg
authors.initials: J
authors.lastname: Hockemeyer
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.forename: Jag
authors.initials: J
authors.lastname: Heer
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000818:Animals; D006207:Half-Life; D006801:Humans; D008862:Microsomes, Liver / Q000378:metabolism; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry; D014970:Xanthines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D008996:Monoamine Oxidase Inhibitors; D014970:Xanthines; D014867:Water; D008995:Monoamine Oxidase
keywords: adenosine receptors; antagonists; inhibitors; monoamine oxidases; multitarget drugs; neurodegenerative diseases