Structure-activity relationships of 2-chloro-N6-substituted-4'-thioadenosine-5'-uronamides as highly potent and selective agonists at the human A3 adenosine receptor.
We have established structure-activity relationships of novel 4'-thionucleoside analogues as the A(3) adenosine receptor (AR) agonists. Binding affinity, selectivity toward other AR subtypes, and efficacy in inhibition of adenylate cyclase were studied. From this study, 2-chloro-N(6)-methyl-4'-thioadenosine-5'-methyluronamide (36a) emerged as the most potent and selective agonist at the human A(3) AR. We have also revealed that, similar to 4'-oxoadenosine analogues, at least one hydrogen on the 5'-uronamide moiety was necessary for high-affinity binding at the human A(3) AR, presumably to allow this group to donate a H bond within the binding site. Furthermore, bulky substituents on the 5'-uronamide reduced binding affinity, but in some cases large 5'-uronamide substituents, such as substituted benzyl and 2-phenylethyl groups, maintained moderate affinity with reduced efficacy, leading to A(3) AR partial agonists or antagonists. In several cases for which the corresponding 4'-oxonucleosides have been studied, the 4'-thionucleosides showed higher binding affinity to the A(3) AR.
Jeong
Lak Shin
LS
Laboratory of Medicinal Chemistry, College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea. lakjeong@ewha.ac.kr
Lee
Hyuk Woo
HW
Jacobson
Kenneth A
KA
Kim
Hea Ok
HO
Shin
Dae Hong
DH
Lee
Jeong A
JA
Gao
Zhan-Guo
ZG
Lu
Changrui
C
Duong
Heng T
HT
Gunaga
Prashantha
P
Lee
Sang Kook
SK
Jin
Dong Zhe
DZ
Chun
Moon Woo
MW
Moon
Hyung Ryong
HR
D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014574:Uronic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D058907:Adenosine A1 Receptor Agonists; D058908:Adenosine A2 Receptor Agonists; D058909:Adenosine A3 Receptor Agonists; D000577:Amides; D014574:Uronic Acids; D000241:Adenosine