SIB 1757

SIB-1757 and SIB-1893: selective, noncompetitive antagonists of metabotropic glutamate receptor type 5.[Pubmed:10381773]

J Pharmacol Exp Ther. 1999 Jul;290(1):170-81.

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 microM compared with an IC50 of >100 microM 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 microM compared with an IC50 of >100 microM 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.

Peripheral and spinal antihyperalgesic activity of SIB-1757, a metabotropic glutamate receptor (mGLUR(5)) antagonist, in experimental neuropathic pain in rats.[Pubmed:10998562]

Neurosci Lett. 2000 Oct 6;292(2):115-8.

Recent studies suggest a role of Group 1 metabotropic glutamate receptors in mediating the development of spinal hypersensitivity in some pain states. Here, the possible role of mGluR(5) receptors in experimental neuropathic pain elicited by ligation of spinal nerves (L(5)/L(6) spinal nerve ligation, SNL) was explored with SIB-1757, a selective mGluR(5) antagonist. SNL-induced tactile allodynia was detected by decreased paw withdrawal thresholds to probing with von Frey filaments and thermal hyperalgesia by decreased paw withdrawal latencies to radiant heat applied to the plantar aspect of the hindpaw. SIB-1757 was given by either intrathecal (i.th.), subcutaneous (s.c.) or intraplantar (i.pl.) injection. In SNL rats, i.th. SIB-1757 produced a partial reversal of tactile allodynia with a shallow dose-response curve ranging over three-orders of magnitude; SIB-1757 was inactive against allodynia when given systemically. SIB-1757 produced full reversal of thermal hyperalgesia in SNL rats following administration either spinally or locally to the injured paw; administration to the contralateral paw had no effect. SIB-1757 did not produce antinociception in either the SNL or sham-operated rats by any route. These data suggest a significant modulation of thermal hyperalgesia by mGluR(5) antagonists, consistent with reports that this receptor may be associated with afferent C-fibers. The less impressive effect seen on tactile allodynia, likely to be mediated by large fiber input, suggests that the observed modulation may be related to blockade of mGluR(5)-mediated spinal sensitization. These results do not support the involvement of these receptors in modulation of acute nociception but suggest the possibility of a role for Group I mGluRs in the mediation of aspects of neuropathic pain which may be associated with C-fiber inputs.