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

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 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; 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 (K-i A1 351 nm, A(2A) 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.