Design and Synthesis of Novel Dual-Action Compounds Targeting the Adenosine A 2A Receptor and Adenosine Transporter for Neuroprotection
Journal
ChemMedChem
Journal Volume
6
Journal Issue
8
Pages
1390-1400
Date Issued
2011
Author(s)
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
Abstract
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.
Subjects
Adenosine signaling; Designed multiple ligand; Neuroprotection; Pharmacophore analysis; Structure-activity relationships
SDGs
Other Subjects
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
Type
journal article