The G-protein-biased agents PZM21 and TRV130 are partial agonists of μ-opioid receptor-mediated signalling to ion channels

Background and Purpose: Opioids remain the most efficient medications against severe pain; they act on receptors that couple to heterotrimeric G-proteins in the G_αi/o family. Opioids exert many of their acute effects through modulating ion channels via G_βγ subunits. Many of their side effects are attributed to β-arrestin recruitment. Several biased agonists that do not recruit β-arrestins, but activate G-protein-dependent pathways, have recently been developed. While these compounds have been proposed to be full agonists of G-protein signalling in several high throughput pharmacological assays, their effects were not studied on ion channel targets. Experimental Approach: Here, we used patch-clamp electrophysiology and Ca²⁺ imaging to test the effects of TRV130, PZM21, and herkinorin, three G-protein-biased agonists of μ-opioid receptors, on ion channel targets of G_αi/o/G_βγ signalling. We also studied G-protein dissociation using a FRET-based assay. Key Results: All three biased agonists induced smaller activation of G-protein-coupled inwardly rectifying K⁺ channels (K_ir3.2) and smaller inhibition of transient receptor potential melastatin (TRPM3) channels than the full μ receptor agonist DAMGO. Co-application of TRV130 or PZM21, but not herkinorin, alleviated the effects of DAMGO on both channels. PZM21 and TRV130 also decreased the effect of morphine on K_ir3.2 channels. The Ca_V2.2 channel was also inhibited less by PZM21 and TRV130 than by DAMGO. We also found that TRV130, PZM21, and herkinorin were less effective than DAMGO at inducing dissociation of the G_αi/G_βγ complex. Conclusion and Implications: TRV130, PZM21, and potentially herkinorin are partial agonists of μ receptors.