A series of novel 2-amino-3-benzoylthiophenes (2A3BTs) were screened using a functional assay of A(1)R mediated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in intact CHO cells to identify potential agonistic effects as well as the ability to allosterically modulate the activity of the orthosteric agonist, R-PIA. Two derivatives, 8h and 8i, differing only in terms of the absence or presence of an electron-withdrawing group on the benzoyl moiety of the 2A3BT scaffold, were identified as biased allosteric agonists and positive allosteric modulators of agonist function at the adenosine A(1) receptor (A(1)R) in two different functional assays. Our findings indicate that subtle structural variations can promote functionally distinct receptor conformational states.
Valant, C., Aurelio, L., Devine, S. M., Ashton, T. D., White, J. M., Sexton, P. M., ... Scammells, P. J. (2012). Synthesis and characterization of novel 2-amino-3-benzoylthiophene derivatives as biased allosteric agonists and modulators of the adenosine A1 receptor. Journal of Medicinal Chemistry, 55(5), 2367 - 2375. https://doi.org/10.1021/jm201600e