Low Intrinsic Efficacy Alone Cannot Explain the Improved Side Effect Profiles of New Opioid Agonists

In a recent report in Science Signaling (Gillis, A.,
et al. Low intrinsic efficacy for G protein activation
can explain the improved
side effect profiles of new opioid agonists. Sci. Signaling2020, 13, eaaz314010.1126/scisignal.aaz3140),
it was suggested that low intrinsic agonism, and not biased agonism,
leads to an improvement in the separation of potency in opioid-induced
respiratory suppression versus antinociception. Although many of the
compounds that were tested have been shown to display G protein signaling
bias in prior publications, the authors conclude that because they
cannot detect biased agonism in their cellular signaling studies the
compounds are therefore not biased agonists. Rather, they conclude
that it is low intrinsic efficacy that leads to the therapeutic window
improvement. Intrinsic efficacy is the extent to which an agonist
can stimulate a G protein-coupled receptor response in a system, while
biased agonism takes into consideration not only the intrinsic efficacy
but also the potency of an agonist in an assay. Herein, we have reanalyzed
the data presented in the published work (10.1126/scisignal.aaz3140) [including the recent Erratum (10.1126/scisignal.abf9803)] to derive intrinsic efficacy and bias factors as ΔΔlog(τ/KA) and ΔΔlog(Emax/EC50), respectively. On the basis of this reanalysis, the data support
the conclusion that biased agonism, favoring G protein signaling,
was observed. Moreover, a conservation of rank order intrinsic efficacy
was not observed upon comparing responses in each assay, further suggesting
that multiple active receptor states were present. These observations
agree with prior studies in which oliceridine, PZM21, and SR-17018
were first described as biased agonists with improvement in antinociception
over respiratory suppression in mice. Therefore, the data in the Science Signaling paper provide strong corroborating evidence
that G protein signaling bias may be a means of improving opioid analgesia
while avoiding certain undesirable side effects.