https://scholars.lib.ntu.edu.tw/handle/123456789/364090
標題: | Design and Synthesis of Novel Dual-Action Compounds Targeting the Adenosine A 2A Receptor and Adenosine Transporter for Neuroprotection | 作者: | Chen, Jhih-Bin Liu, Eric Minwei Chern, Ting-Rong Yang, Chieh-Wen Lin, Chia-I Huang, Nai-Kuei Lin, Yun-Lian Chern, Yijuang Lin, Jung-Hsin Fang, Jim-Min JIM-MIN FANG |
關鍵字: | Adenosine signaling; Designed multiple ligand; Neuroprotection; Pharmacophore analysis; Structure-activity relationships | 公開日期: | 2011 | 卷: | 6 | 期: | 8 | 起(迄)頁: | 1390-1400 | 來源出版物: | ChemMedChem | 摘要: | A novel compound, N 6-(4-hydroxybenzyl)adenosine, isolated from Gastrodia elata and which has been shown to be a potential therapeutic agent for preventing and treating neurodegenerative disease, was found to target both the adenosine A 2A receptor (A 2AR) and the equilibrative nucleoside transporter1 (ENT1). As A 2AR and ENT1 are proximal in the synaptic crevice of striatum, where the mutant huntingtin aggregate is located, the dual-action compounds that concomitantly target these two membrane proteins may be beneficial for the therapy of Huntington's disease. To design the desired dual-action compounds, pharmacophore models of the A 2AR agonists and the ENT1 inhibitors were constructed. Accordingly, potentially active compounds were designed and synthesized by chemical modification of adenosine, particularly at the N 6 and C 5' positions, if the predicted activity was within an acceptable range. Indeed, some of the designed compounds exhibit significant dual-action properties toward both A 2AR and ENT1. Both pharmacophore models exhibit good statistical correlation between predicted and measured activities. In agreement with competitive ligand binding assay results, these compounds also prevent apoptosis in serum-deprived PC12 cells, rendering a crucial function in neuroprotection and potential utility in the treatment of neurodegenerative diseases. ? 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. |
URI: | http://www.scopus.com/inward/record.url?eid=2-s2.0-79960660121&partnerID=MN8TOARS http://scholars.lib.ntu.edu.tw/handle/123456789/364090 |
DOI: | 10.1002/cmdc.201100126 | SDG/關鍵字: | adenosine A2a receptor antagonist; equilibrative nucleoside transporter 1; huntingtin; membrane protein; n 6(4 hydroxybenzyl)adenosine; neuroprotective agent; unclassified drug; apoptosis; article; binding assay; chemical modification; degenerative disease; drug activity; drug synthesis; drug targeting; Gastrodia elata; human; human cell; Huntington chorea; ligand binding; neuroprotection; pharmacophore; priority journal; protein targeting; Adenosine; Adenosine A2 Receptor Agonists; Animals; Apoptosis; Drug Design; Equilibrative Nucleoside Transporter 1; Gastrodia; Humans; Models, Chemical; Neuroprotective Agents; PC12 Cells; Rats; Receptor, Adenosine A2A |
顯示於: | 化學系 |
在 IR 系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。