Anti-Inflammatory Activities of 8-Benzylaminoxanthines Showing High Adenosine A2A and Dual A1/A2A Receptor Affinity

Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson’s disease (PD). In the present study, we synthesized 25 novel xanthine derivatives with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potent...

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Published in:International journal of molecular sciences 2023-09, Vol.24 (18), p.13707
Main Authors: Załuski, Michał, Łażewska, Dorota, Jaśko, Piotr, Honkisz-Orzechowska, Ewelina, Kuder, Kamil J., Brockmann, Andreas, Latacz, Gniewomir, Zygmunt, Małgorzata, Kaleta, Maria, Greser, Beril Anita, Olejarz-Maciej, Agnieszka, Jastrzębska-Więsek, Magdalena, Vielmuth, Christin, Müller, Christa E., Kieć-Kononowicz, Katarzyna
Format: Article
Language:English
Subjects:
Adenosine
adenosine A1 receptor
adenosine A2A receptor
anti-inflammatory activity
Chemokines
Cytokines
Drug dosages
Edema
Griess assay
Inflammation
Microwaves
Parkinson's disease
Pathogenesis
phagocytic activity
Tumor necrosis factor-TNF
xanthine derivatives
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Summary:Chronic inflammation plays an important role in the development of neurodegenerative diseases, such as Parkinson’s disease (PD). In the present study, we synthesized 25 novel xanthine derivatives with variable substituents at the N1-, N3- and C8-position as adenosine receptor antagonists with potential anti-inflammatory activity. The compounds were investigated in radioligand binding studies at all four human adenosine receptor subtypes, A1, A2A, A2B and A3. Compounds showing nanomolar A2A and dual A1/A2A affinities were obtained. Three compounds, 19, 22 and 24, were selected for further studies. Docking and molecular dynamics simulation studies indicated binding poses and interactions within the orthosteric site of adenosine A1 and A2A receptors. In vitro studies confirmed the high metabolic stability of the compounds, and the absence of toxicity at concentrations of up to 12.5 µM in various cell lines (SH-SY5Y, HepG2 and BV2). Compounds 19 and 22 showed anti-inflammatory activity in vitro. In vivo studies in mice investigating carrageenan- and formalin-induced inflammation identified compound 24 as the most potent anti-inflammatory derivative. Future studies are warranted to further optimize the compounds and to explore their therapeutic potential in neurodegenerative diseases.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms241813707