Table 2. SR compounds display a range of bias at the human and mouse MOR.
Bias factor parameters of MOR agonists are presented across functional assays. GTPγS binding was determined in membranes from CHO-hMOR or -mMOR cells or from brainstems of C57BL/6J mice. Inhibition of forskolin-stimulated cAMP accumulation was measured in CHO-hMOR cells. βArrestin2 recruitment to the human MOR was determined by the EFC assay performed in the U2OS-βarrestin-hMOR-PathHunter cells and to the mouse MOR by the βarrestin2-eGFP translocation imaging based assay in U20S-βarrestin2-eGFP-mMOR cells. Data are presented as mean ± S.E.M. for ΔLog(τ/KA) values and with 95% confidence intervals for ΔΔlog(τ/KA) values. Assays were run in duplicate or triplicate, n ≥ 3. ΔLog(τ/KA) values were calculated relative to DAMGO within each individual experiment. ΔΔLog(τ/KA) values were then calculated between the indicated assays as described in the methods to propagate error (95% CI). See also: Figures 1 and S3 for the corresponding concentration response curves and Table S2 for corresponding EC50 and EMAX values.
| Agonist | Human MOR | ||||||
|---|---|---|---|---|---|---|---|
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| Δlog(τ/KA) | GTPγS (CHO)/βarr2 | cAMP (CHO)/βarr2 | |||||
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| GTPγS (CHO) | cAMP (CHO) | βarr2 (EFC) | ΔΔlog(τ/KA) | Bias | Δδlog(τ/KA) | Bias | |
| DAMGO | 1 | 1 | |||||
| Sufentanil | 1.42±0.01 | 2.24±0.10 | 2.21±0.16 | −0.78 (−1.28 to −0.29)b | 0.16 | 0.02 (−0.40 to 0.44) | 1.1 |
| Fentanyl | −0.19±0.08 | 1.00±0.13 | 0.56±0.04 | −0.75 (−0.92 to −0.58)d | 0.18 | 0.45 (0.11 to 0.79)a | 2.8 |
| SR-11501 | −0.58±0.02 | −0.28±0.12 | −0.19±0.06 | −0.39 (−0.53 to −0.26)c | 0.41 | −0.09 (−0.39 to 0.21) | 0.81 |
| Morphine | −0.35±0.02 | −0.67±0.07 | −0.46±0.03 | 0.11 (0.02 to 0.20)a | 1.3 | −0.21 (−0.34 to −0.08)b | 0.62 |
| SR-14969 | 0.14±0.11 | −0.48±0.08 | −0.88±0.12 | 1.03 (0.66 to 1.39)d | 11 | 0.40 (0.04 to 0.76)a | 2.5 |
| SR-14968 | 0.70±0.13 | −0.15±0.09 | −0.85±0.07 | 1.55 (1.25 to 1.85)d | 36 | 0.71 (0.46 to 0.96)d | 5.1 |
| SR-15098 | −0.88±0.04 | −1.04±0.11 | −2.34±0.11 | 1.47 (1.18 to 1.75)d | 29 | 1.28 (0.91 to 1.66)d | 19 |
| SR-15099 | −0.81±0.05 | −1.05±0.22 | −2.48±0.06 | 1.68 (1.47 to 1.89)d | 47 | 1.44 (1.10 to 1.77)d | 27 |
| SR-17018 | −0.64±0.06 | −0.92±0.29 | −2.56±0.20 | 1.93 (1.22 to 2.63)d | 85 | 1.60 (0.84 to 2.35)c | 40 |
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| Mouse MOR | |||||||
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| Δlog(τ/KA) | GTPγS (CHO)/βarr2 | GTPγS (brain)/βarr2 | |||||
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| GTPγS (CHO) | GTPγS (brain) | βarr2 (imaging) | Δδlog(τ/KA) | Bias | Δδlog(τ/KA) | Bias | |
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| DAMGO | 1 | 1 | |||||
| Sufentanil | 1.08±0.07 | 1.48±0.22 | 2.33±0.06 | −1.25 (−1.48 to −1.02)d | 0.06 | −0.85 (−1.45 to −0.25)a | 0.14 |
| Fentanyl | −0.44±0.03 | 0.003±0.26 | 0.83±0.08 | −1.27 (−1.56 to −0.99)d | 0.05 | −0.83 (−1.30 to −0.35)b | 0.15 |
| SR-11501 | −0.68±0.02 | −0.41±0.12 | 0.23±0.05 | −0.91 (−1.06 to −0.77)d | 0.12 | −0.64 (−0.99 to −0.29)b | 0.23 |
| Morphine | −0.42±0.07 | −0.04±0.05 | −0.33±0.07 | −0.09 (−0.37 to 0.18) | 0.80 | 0.29 (0.11 to 0.46)b | 1.9 |
| SR-14969 | −0.06±0.05 | 0.41±0.09 | −0.52±0.09 | 0.46 (0.21 to 0.71)b | 2.9 | 0.93 (0.63 to 1.24)c | 8.6 |
| SR-14968 | 0.50±0.08 | 1.22±0.10 | −0.32±0.15 | 0.83 (0.40 to 1.25)b | 6.7 | 1.54 (1.13 to 1.94)d | 34 |
| SR-15098 | −0.94±0.02 | −0.22±0.05 | −1.96±0.19 | 1.03 (0.44 to 1.61)b | 11 | 1.74 (1.36 to 2.12)d | 55 |
| SR-15099 | −0.92±0.02 | −0.25±0.08 | −1.99±0.19 | 1.07 (0.51 to 1.63)b | 12 | 1.74 (1.33 to 2.15)d | 55 |
| SR-17018 | −0.86±0.03 | −0.32±0.08 | −2.33±0.12 | 1.47 (1.12 to 1.82)d | 30 | 2.01 (1.67 to 2.35)d | 102 |
Unpaired, two-tailed t test to vs. DAMGO:
p<0.05,
p<0.01,
p<0.001,
p<0.0001.