title: Design, synthesis, and biological activity of N6-substituted-4'-thioadenosines at the human A3 adenosine receptor.
abstract: A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.
authors.affiliation: Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea. lakjeong@ewha.ac.kr
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Ji Young
authors.initials: JY
authors.lastname: Jung
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Heng T
authors.initials: HT
authors.lastname: Duong
authors.forename: Srikar
authors.initials: S
authors.lastname: Rao
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.forename: Dae Hong
authors.initials: DH
authors.lastname: Shin
authors.forename: Jeong A
authors.initials: JA
authors.lastname: Lee
authors.forename: Prashantha
authors.initials: P
authors.lastname: Gunaga
authors.forename: Sang Kook
authors.initials: SK
authors.lastname: Lee
authors.forename: Dong Zhe
authors.initials: DZ
authors.lastname: Jin
authors.forename: Moon Woo
authors.initials: MW
authors.lastname: Chun
authors.forename: Hyung Ryong
authors.initials: HR
authors.lastname: Moon
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D058909:Adenosine A3 Receptor Agonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D015195:Drug Design; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D043705:Receptor, Adenosine A2A / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D058909:Adenosine A3 Receptor Agonists; D008024:Ligands; D043682:Receptor, Adenosine A1; D043705:Receptor, Adenosine A2A; D011994:Recombinant Proteins; D013872:Thionucleosides; D000242:Cyclic AMP; D000241:Adenosine