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

Abstract

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.

• Authors: Jhih-Bin Chen, Eric Minwei Liu, Ting-Rong Chern, Chieh-Wen Yang, Chia-I Lin, Nai-Kuei Huang, Yun-Lian Lin, Yijuang Chern, Jung-Hsin Lin, Jim-Min Fang
• Journal: ChemMedChem (ChemMedChem) Vol. 6 Issue 8 Pg. 1390-400 (Aug 01 2011) ISSN: 1860-7187 [Electronic] Germany
• PMID: 21692183 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Adenosine A2 Receptor Agonists
• Equilibrative Nucleoside Transporter 1
• N6-(4-hydroxybenzyl)adenine riboside
• Neuroprotective Agents
• Receptor, Adenosine A2A
• SLC29A1 protein, human
• Adenosine

Topics

• Adenosine (analogs & derivatives, chemical synthesis, chemistry, pharmacology)
• Adenosine A2 Receptor Agonists (chemical synthesis, chemistry, pharmacology)
• Animals
• Apoptosis
• Drug Design
• Equilibrative Nucleoside Transporter 1 (antagonists & inhibitors, metabolism)
• Gastrodia (chemistry)
• Humans
• Models, Chemical
• Neuroprotective Agents (chemical synthesis, chemistry, pharmacology)
• PC12 Cells
• Rats
• Receptor, Adenosine A2A (chemistry, metabolism)