Activity of SIB-1757 and SIB-1893 on recombinant mGluRs
| Receptor Subtype | Assay | SIB-1757 | SIB-1893 | ||
|---|---|---|---|---|---|
| EC50 | IC50 | EC50 | IC50 | ||
| μM | |||||
| hmGluR1b | Ca2+ | >100 | >100 | >100 | >100 |
| InsPs | >100 | >100 | >100 | >100 | |
| hmGluR2 | cAMP | >1001-a | >100 | >100 | >100 |
| [35S]GTPγS | >100 | >100 | >100 | >100 | |
| hmGluR3 | [35S]GTPγS | >100 | >100 | >100 | >100 |
| hmGluR4a | cAMP | >1001-a | >100 | 26.41-b | N.D.1-c |
| (20.7, 33.5) | |||||
| hmGluR5a | [35S]GTPγS | >100 | >100 | >100 | >100 |
| Ca2+ | >100 | 0.37 | >100 | 0.29 | |
| (0.28, 0.50) | (0.19, 0.43) | ||||
| InsP | >100 | 3.1 | >100 | 2.3 | |
| (2.5, 3.8) | (2.1, 2.6) | ||||
| hmGluR6 | cAMP | >100 | >100 | >100 | >100 |
| hmGluR7b | cAMP | >1001-a | >100 | >100 | >100 |
| hmGluR8a | cAMP | >1001-a | >100 | >100 | >100 |
Activity of SIB-1757 and SIB-1893 was examined on recombinant mGluRs stably expressed in cell lines. Various functional assays were used, including Ca2+ (Fura-2-loaded cells), cAMP (inhibition of forskolin-mediated elevation of cAMP), InsP accumulation, and [35S]GTPγS binding. For agonist activity determinations (EC50 values), SIB-1757 and SIB-1893 were tested alone, and for the antagonist tests (IC50 values), the compounds were tested in the presence of an ∼EC80 value of agonist (see the text). Data represent the average of three to five separate determinations.
↵1-a In cAMP measurements, SIB-1757 alone potentiated forskolin-stimulated cAMP levels by approximately 20%. This may have been due to a colorimetric interference with the cAMP assay.
↵1-b SIB-1893 inhibited forskolin-elevated cAMP levels at mGluR4 with an EC50 value of 26.4 μM, but the maximal extent of inhibition was 47.3 ± 2.5%.
↵1-c N.D., not determined because an antagonist test cannot be performed if there is an effect in the agonist test.