Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site

Proceedings of the National Academy of Sciences of the United States of America
F KnoflachJ A Kemp

Abstract

We have identified two chemical series of compounds acting as selective positive allosteric modulators (enhancers) of native and recombinant metabotropic glutamate 1 (mGlu1) receptors. These compounds did not directly activate mGlu1 receptors but markedly potentiated agonist-stimulated responses, increasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to localize amino acids in the receptor transmembrane region critical for these enhancing properties. Finally, the compounds potentiated synaptically evoked mGlu1 receptor responses in rat brain slices. The discovery of selective positive allosteric modulators of mGlu1 receptors opens up the possibility to develop a similar class of compounds for other family 3 G protein-coupled receptors.

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Citations

Feb 26, 2005·Psychopharmacology·James N C Kew, John A Kemp
Jun 23, 2004·Biology of the Cell·J-P PinL Prézeau
Jan 20, 2004·European Journal of Pharmacology·Stephan UrwylerJohannes Mosbacher
Mar 5, 2004·European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences·Anders A Jensen, Tracy A Spalding
Sep 12, 2002·European Journal of Pharmacology·David I B KerrRolf H Prager
May 14, 2003·European Journal of Pharmacology·David I B Kerr, Jennifer Ong
May 7, 2003·Progress in Biophysics and Molecular Biology·Arthur D Conigrave, Alison H Franks
Jun 5, 2003·Pharmacology & Therapeutics·Jean-Philippe PinLaurent Prézeau
Jun 27, 2002·Trends in Pharmacological Sciences·Marie-Laure ParmentierJean-Philippe Pin
Sep 12, 2003·Trends in Pharmacological Sciences·Domenico E Pellegrini-Giampietro
Jul 10, 2003·Current Opinion in Neurobiology·Hisato JingamiKosuke Morikawa
Oct 16, 2003·Current Opinion in Pharmacology·Lauren T May, Arthur Christopoulos
Feb 24, 2011·Biochemistry·Michael R WoodCraig W Lindsley
Jan 31, 2012·Acta Pharmacologica Sinica·Lei ChunJian-feng Liu
Apr 30, 2013·Acta Pharmacologica Sinica·Tamas Bartfai, Ming-wei Wang
Apr 3, 2008·Nature Reviews. Drug Discovery·Malin C Lagerström, Helgi B Schiöth
Jan 1, 2009·Nature Reviews. Drug Discovery·P Jeffrey ConnCraig W Lindsley
Aug 2, 2013·Nature Reviews. Drug Discovery·Denise WoottenPatrick M Sexton
Aug 12, 2009·The Journal of Pharmacology and Experimental Therapeutics·Liyun WangStuart Maudsley
Jan 9, 2010·Annual Review of Pharmacology and Toxicology·Colleen M Niswender, P Jeffrey Conn
Oct 3, 2006·Annual Review of Pharmacology and Toxicology·Lauren T MayArthur Christopoulos
May 15, 2008·PloS One·Arthur BikbaevDenise Manahan-Vaughan
Nov 1, 2003·Proceedings of the National Academy of Sciences of the United States of America·Michael J MarinoP Jeffrey Conn
Dec 24, 2003·Proceedings of the National Academy of Sciences of the United States of America·Cyril GoudetJean Philippe Pin
May 3, 2005·The Journal of Biological Chemistry·Cyril GoudetJean-Philippe Pin

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