@article{097c0abe09d7430386bb51de03ce94f9,
title = "Interaction of A3 adenosine receptor ligands with the human multidrug transporter ABCG2",
abstract = "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.",
keywords = "A adenosine receptor, ABC transporter, ABCG2, ATP hydrolysis, Drug transport, Multidrug resistance",
author = "Biebele Abel and Megumi Murakami and Tosh, {Dilip K.} and Jinha Yu and Sabrina Lusvarghi and Campbell, {Ryan G.} and Gao, {Zhan Guo} and Jacobson, {Kenneth A.} and Ambudkar, {Suresh V.}",
note = "Funding Information: We thank George Leiman for editorial assistance. This work was supported by funds from the Intramural Research Program of the National Institutes of Health , National Cancer Institute , Center for Cancer Research [ ZIABC010030 ] and the Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases [ NIDDK , ZIADK31117 ]. Dr. Megumi Murakami was supported in part by a Fellowship from the Japan Society for the Promotion of Science . The computational resources of the NIH HPC Biowulf cluster ( http://hpc.nih.gov ) were used for docking studies. We thank John Lloyd (NIDDK) for mass spectral determinations. We thank Dr. Bryan L. Roth (Univ. North Carolina at Chapel Hill) and National Institute of Mental Health's Psychoactive Drug Screening Program (Contract # HHSN-271-2008-00025-C) for screening data. Funding Information: We thank George Leiman for editorial assistance. This work was supported by funds from the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research [ZIABC010030] and the Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases [NIDDK, ZIADK31117]. Dr. Megumi Murakami was supported in part by a Fellowship from the Japan Society for the Promotion of Science. The computational resources of the NIH HPC Biowulf cluster (http://hpc.nih.gov) were used for docking studies. We thank John Lloyd (NIDDK) for mass spectral determinations. We thank Dr. Bryan L. Roth (Univ. North Carolina at Chapel Hill) and National Institute of Mental Health's Psychoactive Drug Screening Program (Contract # HHSN-271-2008-00025-C) for screening data. Publisher Copyright: {\textcopyright} 2022",
year = "2022",
month = mar,
day = "5",
doi = "10.1016/j.ejmech.2022.114103",
language = "English",
volume = "231",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson s.r.l.",
}