title: 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.affiliation: Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei 106, Taiwan.
authors.forename: Jhih-Bin
authors.initials: JB
authors.lastname: Chen
authors.forename: Eric Minwei
authors.initials: EM
authors.lastname: Liu
authors.forename: Ting-Rong
authors.initials: TR
authors.lastname: Chern
authors.forename: Chieh-Wen
authors.initials: CW
authors.lastname: Yang
authors.forename: Chia-I
authors.initials: CI
authors.lastname: Lin
authors.forename: Nai-Kuei
authors.initials: NK
authors.lastname: Huang
authors.forename: Yun-Lian
authors.initials: YL
authors.lastname: Lin
authors.forename: Yijuang
authors.initials: Y
authors.lastname: Chern
authors.forename: Jung-Hsin
authors.initials: JH
authors.lastname: Lin
authors.forename: Jim-Min
authors.initials: JM
authors.lastname: Fang
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D058908:Adenosine A2 Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015195:Drug Design; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D031668:Gastrodia / Q000737:chemistry; D006801:Humans; D008956:Models, Chemical; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016716:PC12 Cells; D051381:Rats; D043705:Receptor, Adenosine A2A / Q000737:chemistry* / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D033721:Equilibrative Nucleoside Transporter 1; C519742:N6-(4-hydroxybenzyl)adenine riboside; D018696:Neuroprotective Agents; D043705:Receptor, Adenosine A2A; C438649:SLC29A1 protein, human; D000241:Adenosine