A Review of the Therapeutic Potential of Recently Developed G Protein-Biased Kappa Agonists

Conclusion and Future Directions G protein bias may either be affinity/potency-dominant or efficacy-dominant (Table 1). A potential concern is that, despite using the same cellular assays, variations in agonist potency were determined by different, or even the same labs, potentially due to differences in expression levels of the receptor and signaling proteins that occurred during cell passaging. For example the reported arrestin recruitment potency for U69,593 has been reported to be as low as 67.7 nM (Spetea et al., 2017) and as high as 410 nM (Dunn et al., 2018), similarly for U50,488 potency has ranged from 36 to 1000 nM (Dunn et al., 2018; Liu et al., 2019). In our hands the values were slightly different as well, finding the following potencies and efficacies for U50,488 (EC50 = 51.5 ± 12, α = 100 ± 1), nalfurafine (EC50 (nM) = 5.19 ± 1.3, α = 84 ± 7), and salvinorin A (EC50 = 27.5 ± 10, α = 76 ± 9), whilst also confirming super recruitment by GR89,696 (EC50 = 9.90 ± 3.6, α = 112 ± 3), but partial recruitment of dynorphin A (EC50 = 21.0 ± 13, α = 87 ± 5) relative to U50,488 (Figure 3). These potency differences as well as which reference compound is used will impact the calculated bias factor, which is the reason why we did not include bias factors in Table 1. It would be helpful for the field if the endogenous agonist dynorphin A was used as reference compound to ensure...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research

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