Data_Sheet_1_Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity.PDF

<p>Tetrahydropyrazino-annelated theophylline (1,3-dimethylxanthine) derivatives have previously been shown to display increased water-solubility as compared to the parent xanthines due to their basic character. In the present study, we modified this promising scaffold by replacing the 1,3-dimethyl residues by a variety of alkyl groups including combinations of different substituents in both positions. Substituted benzyl or phenethyl residues were attached to the N8 of the resulting 1,3-dialkyl-tetrahydropyrazino[2,1-f ]purinediones with the aim to obtain multi-target drugs that block human A₁ and A_2A adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A₁ ARs, e.g., 15d (PSB-18339, 8-m-bromobenzyl-substituted) displayed a K_i value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A_2A AR affinity. The 8-phenethyl derivative 20h was selective for the A_2A AR (K_i 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A₁ and A_2A ARs with equal potency (K_i A₁, 180 nM; A_2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blocked all three targets, A₁ ARs (K_i 396 nM), A_2A ARs (K_i 1,620 nM), and MAO-B (IC₅₀ 106 nM) with high selectivity vs. the other subtypes (A_2B and A₃ ARs, MAO-A), and can thus be considered as a multi-target drug. Our findings were rationalized by molecular docking studies based on previously published X-ray structures of the protein targets. The new drugs have potential for the treatment of neurodegenerative diseases, in particular Parkinson's disease.