Synthesis of 2-chloro-N6-substituted-4'-thioadenosine-5'-N, N-dialkyluronamides as potent and selective A3 adenosine receptor antagonists.
The highly selective A(3) receptor agonist, 4'-thio-Cl-IB-MECA was successfully converted into selective A(3) receptor antagonists by appending a second N-alkyl group on the 5'-uronamide position. This result indicates that the hydrogen bonding ability of the 5'-uronamide is essential for the conformational change required for the receptor activation. Among compounds tested, a N(6)-(3-bromobenzyl) derivative with 5'-dimethyluronamide exhibited the highest binding affinity (K(i) = 9.32 nM) at the human A(3) AR with very low binding affinities to other AR subtypes.
Choi
Won Jun
WJ
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
Lee
Hyuk Woo
HW
Hou
Xiyan
X
Kim
Hea O K
HO
Jacobson
Kenneth A
KA
Jeong
Lak Shin
LS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry; D058918:Adenosine A3 Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D006860:Hydrogen Bonding; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000378:metabolism; D043684:Receptor, Adenosine A3 / Q000378:metabolism
D058918:Adenosine A3 Receptor Antagonists; D011684:Purine Nucleosides; D043684:Receptor, Adenosine A3; C504222:thio-Cl-IB-MECA; D000241:Adenosine
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