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.
|Original language||English (US)|
|Number of pages||15|
|Journal||Journal of Medicinal Chemistry|
|State||Published - Jan 12 2012|
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery