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

Frontiers in Chemistry
Pierre KochChrista E Müller

Abstract

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 A2A 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 Ki value of 13.6 nM combined with high selectivity. 1-Ethyl-3-propargyl-substituted derivatives exhibited increased A2A AR affinity. The 8-phenethyl derivative 20h was selective for the A2A AR (Ki 149 nM), while the corresponding 8-benzyl-substituted compound 20e (PSB-1869) blocked A1 and A2A ARs with equal potency (Ki A1, 180 nM; A2A, 282 nM). The 1-ethyl-3-methyl-substituted derivative 16a (PSB-18405) bearing a m,p-dichlorobenzyl residue at N8 blo...Continue Reading

References

Dec 1, 1989·Naunyn-Schmiedeberg's Archives of Pharmacology·K N KlotzM Grifantini
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Jun 6, 2000·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·C E MüllerR Sauer
Nov 8, 2007·Chemical Biology & Drug Design·Vigneshwaran Namasivayam, Robert Günther
Dec 27, 2008·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Jacobus P PetzerCornelis J Van der Schyf
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Apr 13, 2010·Bioorganic & Medicinal Chemistry Letters·Stefano AlcaroFernanda Borges
Sep 23, 2010·Handbook of Experimental Pharmacology·Christa E Müller, Kenneth A Jacobson
Sep 23, 2010·Handbook of Experimental Pharmacology·Jiang-Fan Chen, Yijuang Chern
Dec 13, 2012·Expert Opinion on Drug Discovery·Werner J Geldenhuys, Cornelis J Van der Schyf
May 2, 2013·Journal of Medicinal Chemistry·Anne StösselChrista E Müller
May 24, 2013·Drugs·Rosselle Dungo, Emma D Deeks
Mar 22, 2014·Biochemical Society Transactions·Vanessa FlatenDavid Blum
Dec 30, 2014·Current Medicinal Chemistry·Jacobus P Petzer, Anel Petzer
Oct 16, 2015·European Journal of Medicinal Chemistry·Sarel J RobinsonAnna C U Lourens
Mar 6, 2016·Progress in Neuro-psychopharmacology & Biological Psychiatry·Zdeněk Fišar
Mar 13, 2016·Purinergic Signalling·Elisabetta De FilippoChrista E Müller
Dec 10, 2016·Journal of Agricultural and Food Chemistry·Simone CarradoriJacobus P Petzer
Jan 18, 2017·Journal of Enzyme Inhibition and Medicinal Chemistry·Rita MeledduElias Maccioni
Jun 21, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Xuebao WangFaqing Ye
Mar 30, 2018·Nature Communications·Gemma NavarroSergi Ferré

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BETA
column chromatography
X-ray
nuclear magnetic resonance

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