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

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 resi...

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Detalles Bibliográficos
Autores principales: Koch, Pierre, Brunschweiger, Andreas, Namasivayam, Vigneshwaran, Ullrich, Stefan, Maruca, Annalisa, Lazzaretto, Beatrice, Küppers, Petra, Hinz, Sonja, Hockemeyer, Jörg, Wiese, Michael, Heer, Jag, Alcaro, Stefano, Kiec-Kononowicz, Katarzyna, Müller, Christa E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6028563/
https://www.ncbi.nlm.nih.gov/pubmed/29998095
http://dx.doi.org/10.3389/fchem.2018.00206
Descripción
Sumario: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 A(1) and A(2A) adenosine receptors (ARs) and monoaminoxidase B (MAO-B). 1,3-Diethyl-substituted derivatives showed high affinity for A(1) 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 A(1) and A(2A) ARs with equal potency (K(i) A(1), 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, A(1) ARs (K(i) 396 nM), A(2A) ARs (K(i) 1,620 nM), and MAO-B (IC(50) 106 nM) with high selectivity vs. the other subtypes (A(2B) and A(3) 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.