Interaction of A3 adenosine receptor ligands with the human multidrug transporter ABCG2

Biebele Abel, Megumi Murakami, Dilip K. Tosh, Jinha Yu, Sabrina Lusvarghi, Ryan G. Campbell, Zhan Guo Gao, Kenneth A. Jacobson*, Suresh V. Ambudkar*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Various adenosine receptor nucleoside-like ligands were found to modulate ATP hydrolysis by the multidrug transporter ABCG2. Both ribose-containing and rigidified (N)-methanocarba nucleosides (C2-, N6- and 5′-modified), as well as adenines (C2-, N6-, and deaza modified), were included. 57 compounds out of 63 tested either stimulated (50) or inhibited (7) basal ATPase activity. Structure-activity analysis showed a separation of adenosine receptor and ABCG2 activities. The 7-deaza modification had favorable effects in both (N)-methanocarba nucleosides and adenines. Adenine 37c (MRS7608) and (N)-methanocarba 7-deaza-5′-ethyl ester 60 (MRS7343) were found to be potent stimulators of ABCG2 ATPase activity with EC50 values of 13.2 ± 1.7 and 13.2 ± 2.2 nM, respectively. Both had affinity in the micromolar range for A3 adenosine receptor and lacked the 5′-amide agonist-enabling group (37c was reported as a weak A3 antagonist, Ki 6.82 μM). Compound 60 significantly inhibited ABCG2 substrate transport (IC50 0.44 μM). Docking simulations predicted the interaction of 60 with 21 residues in the drug-binding pocket of ABCG2.

Original languageEnglish
Article number114103
JournalEuropean Journal of Medicinal Chemistry
StatePublished - 5 Mar 2022
Externally publishedYes


  • A adenosine receptor
  • ABC transporter
  • ABCG2
  • ATP hydrolysis
  • Drug transport
  • Multidrug resistance


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