TY - JOUR T1 - Structure-Activity Analysis of Biased Agonism at the Human Adenosine A3 Receptor JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.116.103283 SP - mol.116.103283 AU - Jo-Anne Baltos AU - Silvia Paoletta AU - Anh TN Nguyen AU - Karen J Gregory AU - Dilip K Tosh AU - Arthur Christopoulos AU - Kenneth A Jacobson AU - Lauren T May Y1 - 2016/01/01 UR - http://molpharm.aspetjournals.org/content/early/2016/05/02/mol.116.103283.abstract N2 - Biased agonism at G protein-coupled receptors (GPCRs) has significant implications for current drug discovery, but molecular determinants that govern ligand bias remain largely unknown. The adenosine A3 GPCR (A3AR) is a potential therapeutic target for various conditions, including cancer, inflammation and ischemia, but for which biased agonism remains largely unexplored. We now report the generation of bias "fingerprints" for prototypical ribose containing A3AR agonists and rigidified (N)-methanocarba 5'-N-methyluronamide nucleoside derivatives with regards to their ability to mediate different signaling pathways. Relative to the reference prototypical agonist IB-MECA, (N)-methanocarba 5'-N-methyluronamide nucleoside derivatives with significant N6 and/or C2 modifications, including elongated aryl-ethynyl groups, exhibited biased agonism. Significant positive correlation was observed between the C2 substituent length (in Å) and bias towards cell survival. Molecular modeling suggests that extended C2 substituents on (N)-methanocarba 5'-N-methyluronamide nucleosides promotes a progressive outward shift of the A3AR transmembrane domain 2, which may contribute to the subset of A3AR conformations stabilized upon biased agonist binding. ER -