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Structure-activity relationships of 2-chloro-N6-substituted- 4′-thioadenosine-5′-uronamides as highly potent and selective agonists at the human A3 adenosine receptor

Title
Structure-activity relationships of 2-chloro-N6-substituted- 4′-thioadenosine-5′-uronamides as highly potent and selective agonists at the human A3 adenosine receptor
Authors
Jeong L.S.Lee H.W.Jacobson K.A.Kim H.O.Shin D.H.Lee J.A.Gao Z.-G.Lu C.Duong H.T.Gunaga P.Lee S.K.Jin D.Z.Chun M.W.Moon H.R.
Ewha Authors
정낙신이상국
Issue Date
2006
Journal Title
Journal of Medicinal Chemistry
ISSN
0022-2623JCR Link
Citation
vol. 49, no. 1, pp. 273 - 281
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
We have established structure-activity relationships of novel 4′-thionucleoside analogues as the A3 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 A3 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 A3 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 A3 AR. © 2006 American Chemical Society.
DOI
10.1021/jm050595e
Appears in Collections:
약학대학 > 약학과 > Journal papers
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