Design and Synthesis of Novel Dual-Action Compounds Targeting the Adenosine A_(2A) Receptor and Adenosine Transporter for Neuroprotection

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_(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 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_(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.