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Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A 2A and A 3 adenosine receptor ligands

Title
Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A 2A and A 3 adenosine receptor ligands
Authors
Hou X.Majik M.S.Kim K.Pyee Y.Lee Y.Alexander V.Chung H.-J.Lee H.W.Chandra G.Lee J.H.Park S.-G.Choi W.J.Kim H.O.Phan K.Gao Z.-G.Jacobson K.A.Choi S.Lee S.K.Jeong L.S.
Ewha Authors
정낙신최선최원준
SCOPUS Author ID
최선scopus
Issue Date
2012
Journal Title
Journal of Medicinal Chemistry
ISSN
0022-2623JCR Link
Citation
vol. 55, no. 1, pp. 342 - 356
Indexed
SCI; SCIE; SCOPUS WOS scopus
Abstract
Truncated N 6-substituted-4′-oxo- and 4′- thioadenosine derivatives with C2 or C8 substitution were studied as dual acting A 2A and A 3 adenosine receptor (AR) ligands. The lithiation-mediated stannyl transfer and palladium-catalyzed cross-coupling reactions were utilized for functionalization of the C2 position of 6-chloropurine nucleosides. An unsubstituted 6-amino group and a hydrophobic C2 substituent were required for high affinity at the hA 2AAR, but hydrophobic C8 substitution abolished binding at the hA 2AAR. However, most of synthesized compounds displayed medium to high binding affinity at the hA 3AR, regardless of C2 or C8 substitution, and low efficacy in a functional cAMP assay. Several compounds tended to be full hA 2AAR agonists. C2 substitution probed geometrically through hA 2AAR docking was important for binding in order of hexynyl > hexenyl > hexanyl. Compound 4g was the most potent ligand acting dually as hA 2AAR agonist and hA 3AR antagonist, which might be useful for treatment of asthma or other inflammatory diseases. © 2011 American Chemical Society.
DOI
10.1021/jm201229j
Appears in Collections:
약학대학 > 약학과 > Journal papers
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