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

摘要

8-Benzyl-substituted tetrahydropyrazino[2,1-flpurinediones 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,/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,A, 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 A1 351 nM, A_(2A) 322 nM; IC_(50) MAO-B: 260 nM), and may serve as a useful tool for preclinical proof-of-principle studies. Compounds that art at multiple targets relevant for symptomatic as well as disease-modifying treatment of neurodegenerative diseases are expected to show advantages over single-target therapeutics.