Design, synthesis, and biological activity of N6-substituted-4'-thioadenosines at the human A3 adenosine receptor.
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.
Jeong
Lak Shin
LS
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea. lakjeong@ewha.ac.kr
Lee
Hyuk Woo
HW
Kim
Hea Ok
HO
Jung
Ji Young
JY
Gao
Zhan-Guo
ZG
Duong
Heng T
HT
Rao
Srikar
S
Jacobson
Kenneth A
KA
Shin
Dae Hong
DH
Lee
Jeong A
JA
Gunaga
Prashantha
P
Lee
Sang Kook
SK
Jin
Dong Zhe
DZ
Chun
Moon Woo
MW
Moon
Hyung Ryong
HR
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*
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