8‐Benzyltetrahydropyrazino[2, 1‐f]purinediones: Water‐Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases. Issue 8 (9th May 2014)

• Record Type: Journal Article
• Authors: Brunschweiger, Andreas; Koch, Pierre; Schlenk, Miriam; Pineda, Felipe; Küppers, Petra; Hinz, Sonja; Köse, Meryem; Ullrich, Stefan; Hockemeyer, Jörg; Wiese, Michael; Heer, Jag; Müller, Christa E.
• Is Part Of: ChemMedChem. Volume 9:Issue 8(2014:Aug.)
• Page Start: 1704
• Page End: 1724
• Publication Date: 2014-05-09
• Subjects: Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201402082
• Languages: English
• ISSNs: 1860-7179

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <p>8‐Benzyl‐substituted tetrahydropyrazino[2, 1‐<italic>f</italic>]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 A<sub>1</sub>/A<sub>2A</sub> 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‐<italic>f</italic>]purine‐2, 4(1<italic>H</italic>, 3<italic>H</italic>)‐dione (<bold>72</bold>) (human AR: <italic>K</italic><sub>i</sub> A<sub>1</sub> 217 n<sc>M</sc>, A<sub>2A</sub> 233 n<sc>M</sc>; IC<sub>50</sub> MAO‐B: 508 n<sc>M</sc>). Dichlorinated compound <bold>36</bold> [8‐(3, 4‐dichlorobenzyl)‐1, 3‐dimethyl‐6, 7, 8, 9‐tetrahydropyrazino[2, 1‐<italic>f</italic>]purine‐2, 4(1<italic>H</italic>, 3<italic>H</italic>)‐dione] was found to be the best triple‐target drug in rat (<italic>K</italic><sub>i</sub> A<sub>1</sub> 351 n<sc>M</sc>, A<sub>2A</sub> 322 n<sc>m;</sc> IC<sub>50</sub> MAO‐B: 260 n<sc>M</sc>), 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.</p> </abstract>