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

Xiyan Hou, Mahesh S. Majik, Kyunglim Kim, Yuna Pyee, Yoonji Lee, Varughese Alexander, Hwa Jin Chung, Hyuk Woo Lee, Girish Chandra, Jin Hee Lee, Seul Gi Park, Won Jun Choi, Hea Ok Kim, Khai Phan, Zhan Guo Gao, Kenneth A. Jacobson, Sun Choi, Sang Kook Lee, Lak Shin Jeong

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)342-356
Number of pages15
JournalJournal of Medicinal Chemistry
Volume55
Issue number1
DOIs
StatePublished - Jan 12 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    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. (2012). Structure-activity relationships of truncated C2- or C8-substituted adenosine derivatives as dual acting A 2A and A 3 adenosine receptor ligands. Journal of Medicinal Chemistry, 55(1), 342-356. https://doi.org/10.1021/jm201229j