Table 1.
Parameter estimates for pharmacological responses to GLP-1R agonists. Mean ± SEM for 3-parameter fit-derived potency and efficacy estimates from Fig. 1, Fig. 2, Fig. 3. For Emax, where all ligands were full agonists, values are normalised to a “global” Emax obtained for each assay, whereas where only exendin-4 was a full agonist, exendin-F1 and P5 Emax values are expressed relative to exendin-4. Statistical comparisons are by one-way randomised block ANOVA with Tukey’s test. Statistical testing for Emax values was performed on data prior to normalisation. * p < 0.05 versus exendin-4; # p < 0.05 exendin-F1 versus P5. n.c. = not calculable.
| Exendin-4 |
Exendin-F1 |
P5 |
||||
|---|---|---|---|---|---|---|
| Assay and cell model | pEC50 (M) | Emax (%) | pEC50 (M) | Emax (%) | pEC50 (M) | Emax (%) |
| ECD conformational sensor (HEK293-SNAP-GLP-1R) | 7.8 ± 0.1 | 8.5 ± 0.3 | 8.0 ± 0.1 | 6.9 ± 0.4 | 7.2 ± 0.2 *,# | 6.1 ± 0.9 * |
| cAMP (HEK293-SNAP-GLP-1R) | 9.9 ± 0.1 | 95 ± 5 | 8.7 ± 0.1 * | 98 ± 6 | 8.4 ± 0.1 *,# | 92 ± 5 |
| cAMP (PathHunter) | 10.3 ± 0.1 | 97 ± 1 | 9.4 ± 0.1 * | 105 ± 3 | 9.3 ± 0.1 * | 107 ± 2 * |
| β-arrestin2 (PathHunter) | 7.5 ± 0.2 | 100 | 6.4 ± 0.2 * | 15 ± 0 * | 6.3 ± 0 * | 36 ± 3 *,# |
| NanoBiT mini-Gs (HEK293T) | 7.7 ± 0.1 | 100 | 7.1 ± 0.3 | 10 ± 2 * | 7.1 ± 0.1 | 38 ± 7 * |
| NanoBiT β-arrestin2 (HEK293T) | 7.4 ± 0.1 | 100 | n.c. | n.c. | 6.8 ± 0.2 * | 46 ± 7 * |
| Internalisation by microscopy (HEK293-SNAP-GLP-1R) | 8.3 ± 0.1 | 93 ± 8 | 7.2 ± 0.1 * | 17 ± 4 * | 6.8 ± 0.2 * | 64 ± 5 *,# |
| Internalisation by DERET (HEK293-SNAP-GLP-1R) | 8.5 ± 0.2 | 100 | n.c. | n.c. | n.c. | n.c. |
| Lysosomal redistribution (HEK293-SNAP-GLP-1R) | 8.0 ± 0.2 | 100 | n.c. | n.c. | n.c. | n.c. |