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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.
Front Chem. 2018; 6:206.FC

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 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B 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.

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Authors+Show Affiliations

Koch P
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Brunschweiger A
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Namasivayam V
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Ullrich S
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Maruca A
Dipartimento di Scienze della Salute, Università degli Studi "Magna Græcia" di Catanzaro, Catanzaro, Italy.
Lazzaretto B
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Küppers P
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Hinz S
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Hockemeyer J
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.
Wiese M
Pharmaceutical Institute, Pharmaceutical Chemistry II, University of Bonn, Bonn, Germany.
Heer J
UCB Celltech, UCB Pharma S.A., Slough, United Kingdom.
Alcaro S
Dipartimento di Scienze della Salute, Università degli Studi "Magna Græcia" di Catanzaro, Catanzaro, Italy.
Kiec-Kononowicz K
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.
Müller CE
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, Bonn, Germany.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29998095

Citation

Koch, Pierre, et al. "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, vol. 6, 2018, p. 206.
Koch P, Brunschweiger A, Namasivayam V, et al. Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity. Front Chem. 2018;6:206.
Koch, P., Brunschweiger, A., Namasivayam, V., Ullrich, S., Maruca, A., Lazzaretto, B., Küppers, P., Hinz, S., Hockemeyer, J., Wiese, M., Heer, J., Alcaro, S., Kiec-Kononowicz, K., & Müller, C. E. (2018). 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, 6, 206. https://doi.org/10.3389/fchem.2018.00206
Koch P, et al. Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity. Front Chem. 2018;6:206. PubMed PMID: 29998095.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Probing Substituents in the 1- and 3-Position: Tetrahydropyrazino-Annelated Water-Soluble Xanthine Derivatives as Multi-Target Drugs With Potent Adenosine Receptor Antagonistic Activity. AU - Koch,Pierre, AU - Brunschweiger,Andreas, AU - Namasivayam,Vigneshwaran, AU - Ullrich,Stefan, AU - Maruca,Annalisa, AU - Lazzaretto,Beatrice, AU - Küppers,Petra, AU - Hinz,Sonja, AU - Hockemeyer,Jörg, AU - Wiese,Michael, AU - Heer,Jag, AU - Alcaro,Stefano, AU - Kiec-Kononowicz,Katarzyna, AU - Müller,Christa E, Y1 - 2018/06/26/ PY - 2018/02/28/received PY - 2018/05/22/accepted PY - 2018/7/13/entrez PY - 2018/7/13/pubmed PY - 2018/7/13/medline KW - Alzheimer's disease KW - Parkinson's disease KW - adenosine A1 receptor antagonists KW - adenosine A2A receptor antagonists KW - anellated xanthines KW - caffeine derivatives KW - monoamine oxidase (MAO) B inhibitors KW - tetrahydropyrazino[2, 1-f]purinediones SP - 206 EP - 206 JF - Frontiers in chemistry JO - Front Chem VL - 6 N2 - 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 blocked all three targets, A1 ARs (Ki 396 nM), A2A ARs (Ki 1,620 nM), and MAO-B (IC50 106 nM) with high selectivity vs. the other subtypes (A2B 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. SN - 2296-2646 UR - https://www.unboundmedicine.com/medline/citation/29998095/Probing_Substituents_in_the_1__and_3_Position:_Tetrahydropyrazino_Annelated_Water_Soluble_Xanthine_Derivatives_as_Multi_Target_Drugs_With_Potent_Adenosine_Receptor_Antagonistic_Activity_ DB - PRIME DP - Unbound Medicine ER -