We have investigated the mechanism of inhibition and site of action of the novel human metabotropic glutamate receptor 5 (hmGluR5) antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP), which is structurally unrelated to classical metabotropic glutamate receptor (mGluR) ligands. Schild analysis indicated that MPEP acts in a non-competitive manner. MPEP also inhibited to a large extent constitutive receptor activity in cells transiently overexpressing rat mGluR5, suggesting that MPEP acts as an inverse agonist. To investigate the molecular determinants that govern selective ligand binding, a mutagenesis study was performed using chimeras and single amino acid substitutions of hmGluR1 and hmGluR5. The mutants were tested for binding of the novel mGluR5 radioligand [ Metabotropic glutamate receptors are G protein-coupled receptors that play important roles in regulating the activity of many synapses in the central nervous system. At present, eight mGluR 1 subtypes (mGluR1 through mGluR8) have been cloned and functionally expressed (1, 2). Based on their amino acid sequence homologies, pharmacology, and functional profiles, these subtypes are classified further into three groups. Members of group I (mGluR1 and -5) stimulate the activity of phospholipase C and mobilize intracellular Ca 2ϩ . Members of group II (mGluR2 and -3) and group III (mGluR4, -6, -7, -8) inhibit adenylyl cyclase. Despite the differences in primary structures and functional roles, all mGluRs feature a large conserved N-terminal extracellular domain, which is involved in the recognition of agonists and competitive antagonists (3-8).Most ligands for mGluRs were derived from amino acids and act at the conserved glutamate binding site (9). Recently, novel subtype-selective group I mGluR antagonists emerged that are structurally unrelated to amino acids and to each other. The first non-amino acid-like antagonist described was CPCCOEt (Fig. 1), a selective mGluR1 antagonist (10, 11). CPCCOEt inhibits receptor activity by a non-competitive mechanism which does not affect the binding affinity of glutamate (12, 13). Molecular characterization of the site of inhibition in mGluR1 revealed that CPCCOEt interacts with two non-conserved residues at the top of transmembrane (TM) helix VII (13). The first described selective mGluR5 antagonists, SIB-1757 and SIB-1893 (Fig. 1), are also unrelated to amino acids and were shown to act via a non-competitive mechanism (14).To address the question whether these structurally unrelated mGluR1 and mGluR5 antagonists interact with different sites of the mGluR subtypes or share a common binding site in the 7TM domain, we have studied the binding site and mode of action of the selective mGluR5 antagonist MPEP (15). MPEP is a novel derivative of SIB-1893 with nanomolar potency (Fig. 1); it is an effective antihyperalgesic in animal models of chronic inflammatory pain (16), a neuroprotectant in excitotoxin-induced striatal lesions (17) and an anticonvulsant in several epilepsy models (18). We generated a number of chimeric rec...

Lumiracoxib 100 mg od provided effective relief from the pain of knee OA, with efficacy similar to celecoxib 200 mg od, and was well tolerated.

Lumiracoxib is as effective as indomethacin for treatment of acute gout and may have a better safety and tolerability profile.

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