Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College in Kraków, Medyczna 9, 30-688 Krakow, Poland.
Department of Pharmaceutical & Medicinal Chemistry, Pharma Center Bonn & Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Int J Mol Sci. 2023 Sep 5;24(18):13707. doi: 10.3390/ijms241813707.
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 , 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, A, A, A and A. Compounds showing nanomolar A and dual A/A affinities were obtained. Three compounds, , and , were selected for further studies. Docking and molecular dynamics simulation studies indicated binding poses and interactions within the orthosteric site of adenosine A and A 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 and showed anti-inflammatory activity in vitro. In vivo studies in mice investigating carrageenan- and formalin-induced inflammation identified compound 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.
慢性炎症在神经退行性疾病（如帕金森病）的发展中起着重要作用。在本研究中，我们合成了 25 种新型黄嘌呤衍生物，它们在 C-2、C-8 和 C-位具有不同取代基，作为具有潜在抗炎活性的腺苷受体拮抗剂。这些化合物在所有四种人类腺苷受体亚型（A、A、A 和 A）的放射性配体结合研究中进行了研究。获得了对 A 和双重 A/A 具有纳摩尔亲和力的化合物。选择了三种化合物（ 、 和 ）进行进一步研究。对接和分子动力学模拟研究表明了结合构象和在腺苷 A 和 A 受体的变构位点内的相互作用。体外研究证实了化合物的高代谢稳定性，并且在高达 12.5 μM 的浓度下在各种细胞系（SH-SY5Y、HepG2 和 BV2）中没有毒性。化合物 和 在体外表现出抗炎活性。在研究角叉菜胶和甲醛诱导的炎症的小鼠体内研究中，确定化合物 是最有效的抗炎衍生物。未来的研究需要进一步优化这些化合物，并探索它们在神经退行性疾病中的治疗潜力。
