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~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.