A potent and selective kappa opioid receptor (KOPr) analogue of Salvinorin A, Mesyl Sal B, reduces cocaine-induced hyperactivity and behavioral sensitization to cocaine in male rats without causing aversion, sedation, anxiety, or learning and memory deficits. It does not alter sucrose self-administration. However, it increases immobility in the forced swim test, indicating pro-depressive effects. In male mice, Mesyl Sal B is less potent than Salvinorin A at reducing pain in antinociceptive assays. The compound has fewer side effects and longer in vivo action than Salvinorin A, but its pain-relieving effects are limited.
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.