Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Design, Synthesis, and Evaluation of Analogues with Improved Potency and G-protein Activation Bias at the μ Opioid Receptor
ACS Chemical Neuroscience May 8, 2020 Rachel S Crowley, Andrew P. Riley, Amy F Alder et al.
A series of analogues of kurkinorin, a non-nitrogenous μ opioid receptor (MOR) agonist derived from salvinorin A, were synthesized and tested in vitro for G-protein activation and β-arrestin-2 recruitment. Some compounds showed biased signaling, either toward β-arrestin-2 or G-protein activation. Compound 25 is a potent MOR-selective agonist with G-protein bias, over 100 times more potent than morphine and over 5 times more potent than fentanyl in vitro, and produces antinociception with limited tolerance development in vivo, despite lacking a basic nitrogen or other ionizable groups typical of opioid ligands.