Design and synthesis of novel dual-action compounds targeting the adenosine A(2A) receptor and adenosine transporter for neuroprotection

• Published in: ChemMedChem Vol. 6; no. 8; pp. 1390 - 1400
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Germany 01.08.2011
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Adenosine A2 Receptor Agonists - chemical synthesis; Adenosine A2 Receptor Agonists - chemistry; Adenosine A2 Receptor Agonists - pharmacology; Animals; Apoptosis; Drug Design; Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors; Equilibrative Nucleoside Transporter 1 - metabolism; Gastrodia - chemistry; Humans; Models, Chemical; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; PC12 Cells; Rats; Receptor, Adenosine A2A - chemistry; Receptor, Adenosine A2A - metabolism
• ISSN: 1860-7187
• DOI: 10.1002/cmdc.201100126

A novel compound, N⁶-(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(2A) R) and the equilibrative nucleoside transporter 1 (ENT1). As A(2A) R 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(2A) R agonists and the ENT1 inhibitors were constructed. Accordingly, potentially active compounds were designed and synthesized by chemical modification of adenosine, particularly at the N⁶ and C⁵' positions, if the predicted activity was within an acceptable range. Indeed, some of the designed compounds exhibit significant dual-action properties toward both A(2A) R 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.