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

Abstract

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 A1 /A2A 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-f]purine-2,4(1H,3H)-dione (72) (human AR: Ki A1 217 nM, A2A 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 (Ki A1 351 nM, A2A 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.

History and Perspectives of A2AAdenosine Receptor Antagonists as Potential Therapeutic Agents

“…CSC displayed good A 2A AR affinity ( K i = 54 nM) and potency toward MAO‐B (IC 50 = 70 nM, see Table ) . Considering that caffeine is essentially devoid of MAO‐B inhibitory activity, the 8‐styryl function is thought to establish important interactions with the enzyme. Indeed saturation of the styryl double bond (whose E geometry was found to be important for MAO‐B activity, as well) led to reduced inhibitory potency .…”

Aminobenzimidazoles and Structural Isomers as Templates for Dual‐Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands To Combat Neurodegenerative Disorders

“…There are also several examples of dual‐active compounds for which the dual‐acting character was attributed only retrospectively. One of the few “rationally designed” examples combined enzyme‐inhibiting properties (for monoamine oxidase B) with GPCR affinity and selectivity (antagonism at the adenosine A 2A receptor) by applying a 4 H ‐3,1‐benzothiazin‐4‐one scaffold . The authors achieved not only receptor subtype selectivity and selectivity toward MAO‐B, but also affinity in the two‐digit nanomolar range at both targets (“balanced affinity”), which is rarely reached due to the above described difficulties.…”

Adenosine A2A Receptor Antagonists in Drug Development

“…Several series of tricyclic pyrimido-and pyrazino-purinediones have been developed with triple inhibition of MAO-B, A 2A -and A 1 ARs ( Brunschweiger et al 2014;Koch et al 2013). The best triple-active compounds were 23-25 (see Table 3.1).…”