DOI: 10.1002/cmdc.201402082 8-Benzyltetrahydropyrazino[2,1-f]purinediones: Water- Soluble Tricyclic Xanthine Derivatives as Multitarget Drugs for Neurodegenerative Diseases Andreas Brunschweiger, [a] Pierre Koch, [a] Miriam Schlenk, [a] Felipe Pineda, [b] Petra Küppers, [a] Sonja Hinz, [a] Meryem Kçse, [a] Stefan Ullrich, [a] Jçrg Hockemeyer, [a] Michael Wiese, [b] Jag Heer, [c] and Christa E. Müller* [a] Introduction Adenosine is a modulator of many physiological and patho- physiological processes exhibiting central nervous system (CNS) depressant, cardiodepressant, antidiuretic, and immuno- modulatory effects. [1] The nucleoside exerts its effects through activation of specific G protein-coupled cell membrane recep- tors termed A 1 ,A 2A ,A 2B , and A 3 adenosine receptors (ARs). [2] The different AR subtypes show distinct tissue and cell distri- bution. The dominant subtypes in the central nervous system (CNS) are A 1 and A 2A , whereas A 2B and A 3 ARs typically display low expression levels in the brain. A 1 ARs are highly expressed in many regions of the brain including cortex, hippocampus, and caudate–putamen, but also in several peripheral organs and tissues, such as the heart, lung, kidney, and fat cells. [2] Po- tential therapeutic applications of selective A 1 AR antagonists include renal and cardiac failure, and the treatment of cogni- tive dysfunction, as observed in Alzheimer’s disease (AD), due to their CNS stimulatory effects. [3, 4] A 2A ARs show a restricted ex- pression in the brain with high levels in the basal ganglia, where they are co-expressed and form heteromers with dopa- mine D 2 receptors. [5–7] Blockade of A 2A ARs has shown beneficial effects in animal models and in clinical studies of Parkinson’s disease (PD). [8–10] In addition, A 2A AR antagonists were found to exhibit neuroprotective effects in preclinical studies and may therefore exert disease-modifying properties in neurodegener- ative disorders such as PD and AD. [11–14] Monoamine oxidases A and B (MAO-A and MAO-B) are fla- vine adenine dinucleotide (FAD)-dependent mitochondrial en- zymes. They catalyze the oxidative deamination of various amine neurotransmitters, such as (nor)epinephrine, dopamine, and serotonin, and of xenobiotic arylalkylamines, including 2-phenylethylamine and tryptamine. [15] Nonselective inhibitors of MAO, for example, tranylcypromine, and selective MAO-A in- hibitors, for example, moclobemide, are used for the treatment of depression. Selective MAO-B inhibitors are applied as ad- junctive therapeutics for PD in combination with the prodrug levodopa to increase its bioavailability and that of its active metabolite dopamine. Besides the irreversible MAO-B inhibitors selegiline (1a) and rasagiline, reversible inhibitors such as laza- bemide (1b) and safinamide (1c, Figure 1) have been devel- 8-Benzyl-substituted tetrahydropyrazino[2,1-f]purinediones were designed as tricyclic xanthine derivatives containing a basic nitrogen atom in the tetrahydropyrazine ring to im- prove water solubility. A library of 69 derivatives was prepared and evaluated in radioligand binding studies at adenosine re- ceptor (AR) subtypes and for their ability to inhibit monoamine oxidases (MAO). Potent dual-target-directed A 1 /A 2A 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-tetra- hydropyrazino[2,1-f]purine-2,4(1H,3H)-dione (72) (human AR: K i A 1 217 nm,A 2A 233 nm ; IC 50 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 (K i A 1 351 nm,A 2A 322 nm; IC 50 MAO-B : 260 nm), and may serve as a useful tool for pre- clinical proof-of-principle studies. Compounds that act at multi- ple targets relevant for symptomatic as well as disease-modify- ing treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics. [a] Dr. A. Brunschweiger, + Dr. P. Koch, ++ Dr. M. Schlenk, Dr. P. Küppers, Dr. S. Hinz, Dr. M. Kçse, Dr. S. Ullrich, Dr. J. Hockemeyer, Prof. Dr. C. E. Müller Pharmaceutical Chemistry I, Pharmaceutical Institute PharmaCenter Bonn, University of Bonn An der Immenburg 4, 53121 Bonn (Germany) E-mail : christa.mueller@uni-bonn.de [b] Dr. F. Pineda, Prof. Dr. M. Wiese Pharmaceutical Chemistry II, Pharmaceutical Institute PharmaCenter Bonn, University of Bonn An der Immenburg 4, 53121 Bonn (Germany) [c] Dr. J. Heer CNS Research, Medicinal Chemistry & Lead Generation, UCB S.A. Chemin du Foriest, 1420 Braine l’Alleud (Belgium) [ + ] Current address: Faculty for Chemistry and Chemical Biology TU Dortmund, Otto-Hahn-Straße 6, 44227 Dortmund (Germany) [ ++ ] Current address: Institute of Pharmaceutical Sciences, Faculty of Science Eberhard Karls Universität Tübingen Auf der Morgenstelle 8, 72076 Tübingen (Germany) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cmdc.201402082.  2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim ChemMedChem 2014, 9, 1704 – 1724 1704 CHEMMEDCHEM FULL PAPERS