title: Discovery of New Human A(2A) Adenosine Receptor Agonists: Design, Synthesis, and Binding Mode of Truncated 2-Hexynyl-4'-thioadenosine.
abstract: The truncated C2- and C8-substituted-4'-thioadenosine derivatives 4a-d were synthesized from D-mannose, using palladium-catalyzed cross coupling reactions as key steps. In this study, an A(3) adenosine receptor (AR) antagonist, truncated 4'-thioadenosine derivative 3 was successfully converted into a potent A(2A)AR agonist 4a (K(i) = 7.19 ± 0.6 nM) by appending a 2-hexynyl group at the C2-position of a derivative of 3 that was N(6)-substituted. However, C8-substitution greatly reduced binding affinity at the human A(2A)AR. All synthesized compounds 4a-d maintained their affinity at the human A(3)AR, but 4a was found to be a competitive A(3)AR antagonist/A(2A)AR agonist in cyclic AMP assays. This study indicates that the truncated C2-substituted-4'-thioadenosine derivatives 4a and 4b can serve as a novel template for the development of new A(2A)AR ligands.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Xiyan
authors.initials: X
authors.lastname: Hou
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Varughese
authors.initials: V
authors.lastname: Alexander
authors.forename: Kyunglim
authors.initials: K
authors.lastname: Kim
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Seul-Gi
authors.initials: SG
authors.lastname: Park
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Lee
authors.forename: Lena S
authors.initials: LS
authors.lastname: Yoo
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong