title: 8-Substituted 1,3-dimethyltetrahydropyrazino[2,1-f]purinediones: Water-soluble adenosine receptor antagonists and monoamine oxidase B inhibitors.
abstract: Multitarget approaches, i.e., addressing two or more targets simultaneously with a therapeutic agent, are hypothesized to offer additive therapeutic benefit for the treatment of neurodegenerative diseases. Validated targets for the treatment of Parkinson's disease are, among others, the A2Aadenosine receptor (AR) and the enzyme monoamine oxidase B (MAO-B). Additional blockade of brain A1ARs may also be beneficial. We recently described 8-benzyl-substituted tetrahydropyrazino[2,1-f]purinediones as a new lead structure for the development of such multi-target drugs. We have now designed a new series of tetrahydropyrazino[2,1-f]purinediones to extensively explore their structure-activity-relationships. Several compounds blocked human and rat A1and A2AARs at similar concentrations representing dual A1/A2Aantagonists with high selectivity versus the other AR subtypes. Among the best dual A1/A2AAR antagonists were 8-(3-(4-chlorophenyl)propyl)-1,3-dimethyl-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (41, Kihuman A1: 65.5nM, A2A: 230nM; Kirat A1: 352nM, A2A: 316nM) and 1,3-dimethyl-8-((2-(thiophen-2-yl)thiazol-4-yl)methyl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (57, Kihuman A1: 642nM, A2A: 203nM; Kirat A1: 166nM, A2A: 121nM). Compound 57 was found to be well water-soluble (0.7mg/mL) at a physiological pH value of 7.4. One of the new compounds showed triple-target inhibition: (R)-1,3-dimethyl-8-(2,1,3,4-tetrahydronaphthalen-1-yl)-6,7,8,9-tetrahydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (49) was about equipotent at A1and A2AARs and at MAO-B (Kihuman A1: 393nM, human A2A: 595nM, IC50human MAO-B: 210nM) thus allowing future in vivo explorations of the intended multi-target approach.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Brunschweiger
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Pierre
authors.initials: P
authors.lastname: Koch
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schlenk
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Rafehi
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Hamid
authors.initials: H
authors.lastname: Radjainia
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Küppers
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Sonja
authors.initials: S
authors.lastname: Hinz
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Felipe
authors.initials: F
authors.lastname: Pineda
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Wiese
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Hockemeyer
authors.affiliation: CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A., Chemin du Foriest, 1420 Braine l'Alleud, Belgium.
authors.forename: Jag
authors.initials: J
authors.lastname: Heer
authors.affiliation: CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A., Chemin du Foriest, 1420 Braine l'Alleud, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Denonne
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany. Electronic address: christa.mueller@uni-bonn.de.
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D008996:Monoamine Oxidase Inhibitors; D011687:Purines; D011719:Pyrazines; D043705:Receptor, Adenosine A2A; D014867:Water; D008995:Monoamine Oxidase
keywords: Alzheimer’s disease; Anellated xanthines; Caffeine derivatives; Heterocycles; Neurodegenerative disease; Parkinson’s disease: synthesis; Polypharmacology; Water-solubility; Xanthines