Previous structure-activity relationship (SAR) studies identified the first centrally acting, non-nitrogenous μ-opioid receptor (MOR) agonist, kurkinorin ( ), derived from salvinorin A. In an effort to further probe the physiological effects induced upon activation of MORs with this nonmorphine scaffold, a variety of analogues were synthesized and evaluated for their ability to activate G-proteins and recruit β-arrestin-2 upon MOR activation. Through these studies, compounds that are potent agonists at MORs and either biased toward β-arrestin-2 recruitment or biased toward G-protein activation have been identified. One such compound, , has potent activity and selectivity at the MOR over KOR with bias for G-protein activation. Impressively, is over 100× more potent than morphine and over 5× more potent than fentanyl and elicits antinociception with limited tolerance development . This is especially significant given that lacks a basic nitrogen and other ionizable groups present in other opioid ligand classes.