TY - JOUR T1 - SIB-1757 and SIB-1893: Selective, Noncompetitive Antagonists of Metabotropic Glutamate Receptor Type 5 JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 170 LP - 181 VL - 290 IS - 1 AU - Mark A. Varney AU - Nicholas D. P. Cosford AU - Christine Jachec AU - Sara P. Rao AU - Aida Sacaan AU - Fen-Fen Lin AU - Leo Bleicher AU - Emily M. Santori AU - Peter J. Flor AU - Hans Allgeier AU - Fabrizio Gasparini AU - Rainer Kuhn AU - Stephen D. Hess AU - Gönül Veliçelebi AU - Edwin C. Johnson Y1 - 1999/07/01 UR - http://jpet.aspetjournals.org/content/290/1/170.abstract N2 - 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 μM compared with an IC50 of >100 μM 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 IC50of 0.29 μM compared with an IC50 of >100 μM 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, α-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. The American Society for Pharmacology and Experimental Therapeutics ER -