Showing papers by "Gonul Velicelebi published in 1999"
TL;DR: 2-methyl-6-(phenylethynyl)-pyridine is described as a potent, selective and systemically active antagonist for the metabotropic glutamate receptor subtype 5 (mGlu5) and in rat neonatal brain slices, MPEP inhibited DHPG-stimulated PI hydrolysis with a potency and selectivity similar to that observed on human mGlu receptors.
745 citations
Journal Article•
TL;DR: Cell lines expressing the human metabotropic glutamate receptor subtype 5a and hmGluR1b were used as targets in an automated high-throughput screening system that measures changes in intracellular Ca2+ ([Ca2+]i) using fluorescence detection, and the first description of highly selective, noncompetitive mGLUR5 antagonists was described.
Abstract: 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.
184 citations
Patent•
30 Sep 1999TL;DR: In this paper, the use of selective mGluR5 antagonists for the treatment of pain and anxiety, and the using of mgluR antagonists for pain, whereby the analgesic effect is achieved by interaction of said antagonists primarily or predominantly at peripheral mglR receptors.
Abstract: The invention provides the use of selective mGluR5 antagonists for the treatment of pain and anxiety, and the use of mGluR antagonists for the treatment of pain, whereby analgesic effect is achieved by interaction of said antagonists primarily or predominantly at peripheral mGluR receptors.
38 citations
TL;DR: This chapter describes the experimental methods with particular emphasis on the validation of the assay for human VGCCs, NAChRs, and NMDA receptors.
Abstract: Publisher Summary Changes in intracellular free calcium concentration ([Ca 2+ ] i ) play a crucial role in cellular physiology. A number of cell surface receptors and channels are known to regulate [Ca 2+ ] i through different molecular mechanisms. Therefore, the functional and pharmacologic properties of many of these cell surface receptors and ion channels can be studied effectively by measuring changes in [Ca 2+ ] i in intact cells. For drug discovery efforts, several ion channel and receptor systems have been targeted that play different roles in neuronal physiology and pathophysiology. These molecular targets include voltage- and ligand-gated ion channels: the human neuronal voltage-gated calcium channels (VGCCs), ligand-gated nicotinic acetylcholine receptor channels (NAChRs), ionotropic N -methyl-D-aspartic acid (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and kainate-type excitatory amino acid receptor (EAA) channels. All of these channels mediate elevation of [Ca 2+ ] i via Ca 2+ influx from the extracellular medium upon depolarization or activation by agonist. This chapter describes the experimental methods with particular emphasis on the validation of the assay for human VGCCs, NAChRs, and NMDA receptors.
28 citations
5 citations
Patent•
30 Sep 1999
TL;DR: In this article, l'invention porte sur l'utilisation selective d'antagonistes selectifs du mGluR5 for le traitement de la douleur et de l'angoisse, leur effet analgesique provenant d'une interaction desdits antagonistes principalement ou de maniere preponderante avec les recepteurs peripheriques.
Abstract: L'invention porte sur l'utilisation selective d'antagonistes selectifs du mGluR5 pour le traitement de la douleur et de l'angoisse et sur l'utilisation d'antagonistes du mGluR pour le traitement de la douleur, leur effet analgesique provenant d'une interaction desdits antagonistes principalement ou de maniere preponderante avec les recepteurs peripheriques du mGluR.