Table 1.
Summary of GPR40 ligand pharmacology and ex vivo response.
| Ligand | Binding (in vitro) |
IP3 (in vitro) |
cAMP (in vitro) |
tGLP-1 (ex vivo) |
|||||||
|---|---|---|---|---|---|---|---|---|---|---|---|
| [3H]L358 LogIC50 | [3H]AM-1638 LogIC50 | ||||||||||
| LogEC50 | Emax | LogEC50 | Emax | WT | GPR40 (−/−) | ||||||
| Endogenous | ALA | n.d. | n.d. | −4.8 ± 0.19 | 53 ± 4 | >−3 | 1.39 ± 0.4 | 1.4 ± 0.06a | 1.0 ± 0.04a | ||
| DHA | n.d. | n.d. | −4.9 ± 0.24 | 56 ± 6 | >−3 | 1.50 ± 0.5 | n.d | n.d | |||
| Orthosteric | TAK-875 | −7.7 ± 0.05 | (pos) | −7.9 ± 0.07 | (neg) | −7.9 ± 0.14 | 98 ± 4 | >−5 | 0.13 ± 0.6 | 1.5 ± 0.08 | 1.1 ± 0.12 |
| MK-2305 | −7.5 ± 0.05 | (pos) | −7.7 ± 0.07 | (neg) | −7.9 ± 0.24 | 68 ± 5 | >−5 | 0.70 ± 0.4 | 2.8 ± 0.42 | 1.1 ± 0.06 | |
| AM-8182 | −7.6 ± 0.03 | (pos) | −8.2 ± 0.17 | (neg) | −7.3 ± 0.11 | 171 ± 9 | >−5 | 1.48 ± 0.6 | 1.4 ± 0.19 | 1.4 ± 0.14 | |
| Ago-allosteric | AM-1638 | −7.6 ± 0.05 | (neg) | −7.5 ± 0.07 | (pos) | −7.6 ± 0.20 | 170 ± 14 | −6.8 ± 0.13 | 13.01 ± 1.1 | 3.0 ± 0.54 | 1.1 ± 0.07 |
| AM-5262 | −8.1 ± 0.18 | (neg) | −8.0 ± 0.05 | (pos) | −7.7 ± 0.19 | 179 ± 14 | −7.0 ± 0.13 | 12.63 ± 0.1 | 4.6 ± 0.77 | 1.2 ± 0.13 | |
Data are representative of two or more experiments, and expressed as mean ± SEM. n.d; not determined – binding was not carried out with the endogenous ligands, and ex vivo tGLP-1 release was not carried out with DHA. (pos) and (neg) indicates positive or negative competitive binding with radio labeled ligand. Ex vivo tGLP-1 release (fold change) as determined with 1 μM ligand, aexcept for ALA which was 30 μM.