Design and synthesis of N(6)-substituted-4'-thioadenosine-5'-uronamides as potent and selective human A(3) adenosine receptor agonists.
On the basis of a bioisosteric rationale, 4'-thionucleoside analogues of IB-MECA (N(6)-(3-Iodo-benzyl)-9-(5'-methylaminocarbonyl-beta-d-ribofuranosyl)adenine), which is a potent and selective A(3) adenosine receptor (AR) agonist, were synthesized from d-gulonic acid gamma-lactone. The 4'-thio analogue (5h) of IB-MECA showed extremely high binding affinity (K(i)=0.25 nM) at the human A(3)AR and was more potent than IB-MECA (K(i)=1.4 nM). Bulky substituents at the 5'-uronamide position, such as cyclohexyl and 2-methylbenzyl, in this series of 2-H nucleoside derivatives were tolerated in A(3)AR binding, although small alkyl analogues were more potent.
Choi
Won Jun
WJ
Department of Bioinspired Science and Division of Life and Pharmaceutical Sciences, College of Pharmacy, Ewha Womans University, Seoul 120-750, Republic of Korea.
Lee
Hyuk Woo
HW
Kim
Hea Ok
HO
Chinn
Moshe
M
Gao
Zhan-Guo
ZG
Patel
Amit
A
Jacobson
Kenneth A
KA
Moon
Hyung Ryong
HR
Jung
Young Hoon
YH
Jeong
Lak Shin
LS
D058909:Adenosine A3 Receptor Agonists; D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D011869:Radioligand Assay; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013872:Thionucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D058909:Adenosine A3 Receptor Agonists; D000577:Amides; D013872:Thionucleosides