A novel class of positive allosteric modulators of metabotropic glutamate receptor subtype 1 interact with a site distinct from that of negative allosteric modulators.

Molecular Pharmacology
Kamondanai HemstapatP Jeffrey Conn

Abstract

We recently reported a novel class of compounds, represented by 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CD-PPB), that act as positive allosteric modulators (potentiators) of metabotropic glutamate receptor (mGluR) subtype 5. Studies of CDPPB analogs revealed that some compounds in this series serve also as positive allosteric modulators of mGluR1. Although CDPPB is selective for mGluR5 relative to other mGluR subtypes, several CDPPB analogs also showed 2.5-fold potentiation of glutamate-induced calcium transients in cells expressing mGluR1 at 10 muM, with 4-nitro-N-(1,4-diphenyl-1H-pyrazol-5-yl)benzamide (VU-71) being selective for mGluR1. In previous studies, we found that two structural classes of mGluR5-selective allosteric potentiators, including CDPPB, share a common binding site with the allosteric mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine. Negative allosteric modulators of mGluR1, regardless of structural class, have been reported to bind to a common allosteric antagonist site on this receptor. However, neither the novel CDPPB analogs nor previously identified allosteric mGluR1 potentiators [e.g., (S)-2-(4-fluorophenyl)-1-(toluene-4-sulfonyl)pyrrolidine (Ro 67-7476), ethyl diphenylacetylcarbamate (R...Continue Reading

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Citations

Jan 31, 2012·Acta Pharmacologica Sinica·Lei ChunJian-feng Liu
Mar 20, 2009·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Jennifer E AyalaP Jeffrey Conn
Jan 1, 2009·Nature Reviews. Drug Discovery·P Jeffrey ConnCraig W Lindsley
Sep 6, 2008·The Journal of Pharmacology and Experimental Therapeutics·Ashley E BradyCraig W Lindsley
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
Sep 2, 2014·Nature Reviews. Drug Discovery·P Jeffrey ConnColleen M Niswender
Dec 21, 2011·The Journal of Physiology·Keiko YasumatsuYuzo Ninomiya
Feb 14, 2013·Molecular and Cellular Endocrinology·Yumei XiongMargrit Schwarz
Sep 21, 2013·Drug Discovery Today. Technologies·Darren W Engers, Craig W Lindsley
Mar 6, 2012·Bioorganic & Medicinal Chemistry Letters·Matthew J FisherEllen van der Aar
Dec 5, 2012·Journal of Neurochemistry·Kwang H AhnDebra A Kendall
Oct 1, 2013·Neurobiology of Disease·Hilary Highfield Nickols, P Jeffrey Conn
May 30, 2012·Neuropharmacology·C VolpiF Fallarino
Mar 25, 2017·International Journal of Molecular Sciences·Juan ZouJenny J Yang
Mar 17, 2018·Molecular Pharmacology·Daniel E O'BrienP Jeffrey Conn
Apr 10, 2007·The Journal of Pharmacology and Experimental Therapeutics·Kamondanai HemstapatP Jeffrey Conn
Mar 27, 2015·Molecular Pharmacology·Karen J Gregory, P Jeffrey Conn
Aug 9, 2019·Current Topics in Medicinal Chemistry·Zoltán OrgovánGyörgy M Keserű
Jul 21, 2020·ChemMedChem·Zoltán OrgovánGyörgy M Keserű
Mar 23, 2019·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Claudia Llinas Del TorrentGary Tresadern

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