J Pharmacol Exp Ther 1999 Jul;290(1):170-81 |
SIB-1757 and SIB-1893: selective, noncompetitive antagonists of
metabotropic glutamate receptor type 5.
Varney MA, Cosford ND, Jachec C, Rao SP, Sacaan A, Lin FF, Bleicher L, Santori EM, Flor PJ, Allgeier H,
Gasparini F, Kuhn R, Hess SD, Veli elebi G, Johnson EC
SIBIA Neurosciences, Inc., La Jolla, California.
[Medline record in process]
Cell lines expressing the human metabotropic glutamate receptor subtype 5a (hmGluR5a) and hmGluR1b were used as targets
in an automated high-throughput screening (HTS) system that measures changes in intracellular Ca2+ ([Ca2+]i) using
fluorescence detection. This functional screen was used to identify the mGluR5-selective antagonist, SIB-1757
[6-methyl-2-(phenylazo)-3-pyridinol], which inhibited the glutamate-induced [Ca2+]i responses at hmGluR5 with an IC50 of
0.37 &mgr;M compared with an IC50 of >100 &mgr;M at hmGluR1. Schild analysis demonstrated a noncompetitive
mechanism of inhibition. Pharmacophore mapping was used to identify an additional compound, SIB-1893
[(E)-2-methyl-6-(2-phenylethenyl)pyridine], which was also shown to block glutamate-induced increases in [Ca2+]i at
hmGluR5 with an IC50 of 0.29 &mgr;M compared with an IC50 of >100 &mgr;M at hmGluR1. SIB-1757 and SIB-1893
showed little or no activity when tested for agonist and antagonist activity at the other recombinant human mGluR subtypes,
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, kainate, and N-methyl-D-aspartate receptors. In rat neonatal
brain slices, SIB-1757 and SIB-1893 inhibited (S)-3,5-dihydroxyphenylglycine (DHPG)-evoked inositol phosphate
accumulation in hippocampus and striatum by 60% to 80%, with a potency similar to that observed on recombinant mGluR5.
However, in the cerebellum, a brain region with low mGluR5 expression, SIB-1757 failed to inhibit DHPG-evoked inositol
phosphate accumulation. In cultured rat cortical neurons, SIB-1757 and SIB-1893 largely inhibited DHPG-evoked [Ca2+]i
signals, revealing a population of neurons that were less sensitive to SIB-1757 and SIB-1893. This is the first description of
highly selective, noncompetitive mGluR5 antagonists. These compounds will be useful tools in evaluating the role of mGluR5 in
normal physiology and in animal models of disease.