TY - JOUR T1 - Evidence for the Interaction of A<sub>3</sub> Adenosine Receptor Agonists at the Drug-Binding Site(s) of Human P-glycoprotein (ABCB1) JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.118.115295 SP - mol.118.115295 AU - Biebele Abel AU - Dilip K. Tosh AU - Stewart R. Durell AU - Megumi Murakami AU - Shahrooz Vahedi AU - Kenneth A. Jacobson AU - Suresh V. Ambudkar Y1 - 2019/01/01 UR - http://molpharm.aspetjournals.org/content/early/2019/05/24/mol.118.115295.abstract N2 - P-glycoprotein (P-gp) is a multidrug transporter that is expressed on the luminal surface of epithelial cells in the kidney, intestine, bile-canalicular membrane in the liver, blood-brain barrier, and adrenal gland. This transporter utilizes energy from ATPase hydrolysis to efflux from cells a variety of structurally dissimilar hydrophobic and amphipathic compounds, including anticancer drugs. In this regard, understanding the interaction with P-gp of drug entities in development is important and highly recommended in current US Food and Drug Administration guidelines. Here we tested the P-gp interaction of some A3 adenosine receptor agonists that are being developed for the treatment of chronic diseases, including rheumatoid arthritis, psoriasis, chronic pain and hepatocellular carcinoma. Biochemical assays of the ATPase activity of P-gp and by photolabeling P-gp with its transport substrate [125I]-iodoarylazidoprazosin (IAAP) led to the identification of rigidified (N)-methanocarba nucleosides, i.e. compound 3, as a stimulator, and compound 8, as a partial inhibitor of P-gp ATPase activity. Compound 8 significantly inhibited BODIPY-verapamil transport mediated by human P-gp (IC50 2.4 ± 0.6 μM). However, the BODIPY-conjugated derivative of 8 (compound 24) was not transported by P-gp. In silico docking of compounds 3 and 8 was performed using the recently solved atomic structure of Taxol-bound human P-gp. Molecular modeling studies revealed that both compounds 3 and 8 bind in the same region of the drug-binding pocket as Taxol. Thus, this study indicates that A3 adenosine receptor agonists can exhibit varied modulatory effects on P-gp activity depending on structural functionalization.SIGNIFICANCE STATEMENT n/a ER -