Methylphenylethynylpyridine (MPEP) Novartis.
SIBIA and Novartis are investigating the use of excitatory amino acid agonists and antagonists for the metabotropic receptor and the ionotropic receptors AMPA and NMDA. Preliminary experiments indicate they may have potential in the treatment of epilepsy, stroke, anxiety, pain and neurodegenerative disease. Methylphenylethynylpyridine (MPEP) is the lead compound in the series [347212]. Other compounds in the series that arose from the collaboration were SIB-1893, and its equipotent analog, SIB-1757, both of which are subtype-selective, potent antagonists of mGluR5. Chemical derivation of SIB-1893 resulted in the discovery of MPEP, a selective, systemically active noncompetitive mGluR5 antagonist. Studies using these agents have yielded data to support the involvement of mGluR5 in inflammatory mechanical hyperalgesia [311829], [311828], [311823], [311880], [319655]. MPEP is the most potent of these compounds with an IC50 value of 12 nM for inhibition of quisqualate-stimulated phosphoinositide hydrolysis in recombinant human mGluR5a-expressing cells. MPEP exhibited no cross reactivity with mGluR1 and other mGluRs, or against representative NMDA, AMPA and kainate receptors up to concentrations of 100 microM. The compound, administered orally (100 mg/kg) produced a 70% reversal of mechanical hyperalgesia in the Freund's complete adjuvant model of inflammatory pain [319261]. By October 1999, investigations with SIB-1757 and SIB-1893 had been discontinued in favor of MPEP [347212].
Glaxo Wellcome, Medicines Research Centre, Via Fleming 4, 37135 Verona, Italy. fm20244@glaxowellcome.co.uk
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Micheli
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000927:Anticonvulsants / Q000494:pharmacology; D015507:Drugs, Investigational / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D018696:Neuroprotective Agents / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D015507:Drugs, Investigational; D018691:Excitatory Amino Acid Antagonists; C578935:GRM5 protein, human; D018696:Neuroprotective Agents; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; C121465:6-methyl-2-(phenylethynyl)pyridine