Chen, Jhih-BinJhih-BinChenLiu, Eric MinweiEric MinweiLiuChern, Ting-RongTing-RongChernYang, Chieh-WenChieh-WenYangLin, Chia-IChia-ILinHuang, Nai-KueiNai-KueiHuangLin, Yun-LianYun-LianLinChern, YijuangYijuangChernLin, Jung-HsinJung-HsinLinJIM-MIN FANG2018-09-102018-09-102011http://www.scopus.com/inward/record.url?eid=2-s2.0-79960660121&partnerID=MN8TOARShttp://scholars.lib.ntu.edu.tw/handle/123456789/364090A 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.Adenosine signaling; Designed multiple ligand; Neuroprotection; Pharmacophore analysis; Structure-activity relationships[SDGs]SDG3adenosine 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 A2Ajournal article10.1002/cmdc.2011001262-s2.0-79960660121