Table 1

Activity of SIB-1757 and SIB-1893 on recombinant mGluRs

Receptor SubtypeAssaySIB-1757SIB-1893
hmGluR1bCa2+ >100>100>100>100
hmGluR2cAMP>1001-a >100>100>100
hmGluR4acAMP>1001-a >10026.41-b N.D.1-c
(20.7, 33.5)
Ca2+ >1000.37>1000.29
(0.28, 0.50)(0.19, 0.43)
(2.5, 3.8)(2.1, 2.6)
hmGluR7bcAMP>1001-a >100>100>100
hmGluR8acAMP>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.