Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-N,N-dialkyluronamides as human A3 adenosine receptor antagonists.
On the basis of potent and selective A(3) adenosine receptor (AR) antagonist, 2-chloro-N(6)-(3-iodobenzyl)-4'-thioadenosine-5'-N,N-dimethyluronamide, structure-activity relationships were studied for a series of 5'-N,N-dialkyluronamide derivatives, synthesized from D-gulonic gamma-lactone. From this study, it was revealed that removal of the hydrogen bond-donating ability of the 5'-uronamide was essential for the pure A(3)AR antagonism. 5'-N,N-Dimethyluronamide derivatives exhibited higher binding affinity than larger 5'-N,N-dialkyl or 5'-N,N-cycloalkylamide derivatives, indicating that steric factors are crucial in binding to the human A(3)AR. A N(6)-(3-bromobenzyl) derivative 6c (K(i)=9.32 nM) exhibited the highest binding affinity at the human A(3)AR with very low binding affinities to other AR subtypes.
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
Tosh
Dilip K
DK
Pal
Shantanu
S
Choi
Won Jun
WJ
Gao
Zhan-Guo
ZG
Patel
Amit R
AR
Williams
Wanda
W
Jacobson
Kenneth A
KA
Kim
Hee-Doo
HD
D058918:Adenosine A3 Receptor Antagonists; D000577:Amides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014574:Uronic Acids / Q000737:chemistry* / Q000494:pharmacology*
D058918:Adenosine A3 Receptor Antagonists; D000577:Amides; D014574:Uronic Acids