Literature DB >> 22607673

Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM.

Douglas J Sheffler1, Cody J Wenthur, Joshua A Bruner, Sheridan J S Carrington, Paige N Vinson, Kiran K Gogi, Anna L Blobaum, Ryan D Morrison, Mitchell Vamos, Nicholas D P Cosford, Shaun R Stauffer, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley.   

Abstract

Herein we report the discovery and SAR of a novel metabotropic glutamate receptor 3 (mGlu(3)) NAM probe (ML289) with 15-fold selectivity versus mGlu(2). The mGlu(3) NAM was discovered via a 'molecular switch' from a closely related, potent mGlu(5) positive allosteric modulator (PAM), VU0092273. This NAM (VU0463597, ML289) displays an IC(50) value of 0.66 μM and is inactive against mGlu(5).
Copyright © 2012 Elsevier Ltd. All rights reserved.

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Year:  2012        PMID： 22607673      PMCID： PMC3365510          DOI： 10.1016/j.bmcl.2012.04.112

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  27 in total

1.  Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery.

Authors:  Bruce J Melancon; Corey R Hopkins; Michael R Wood; Kyle A Emmitte; Colleen M Niswender; Arthur Christopoulos; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2012-01-06       Impact factor: 7.446

2.  Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries.

Authors:  William Leister; Kimberly Strauss; David Wisnoski; Zhijian Zhao; Craig Lindsley
Journal:  J Comb Chem       Date:  2003 May-Jun

3.  The use of knock-out mice unravels distinct roles for mGlu2 and mGlu3 metabotropic glutamate receptors in mechanisms of neurodegeneration/neuroprotection.

Authors:  Corrado Corti; Giuseppe Battaglia; Gemma Molinaro; Barbara Riozzi; Anna Pittaluga; Mauro Corsi; Manolo Mugnaini; Ferdinando Nicoletti; Valeria Bruno
Journal:  J Neurosci       Date:  2007-08-01       Impact factor: 6.167

4.  Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold.

Authors:  Sameer Sharma; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2008-05-29       Impact factor: 2.823

Review 5.  Metabotropic glutamate receptor antagonists: novel therapeutics for nicotine dependence and depression?

Authors:  Athina Markou
Journal:  Biol Psychiatry       Date:  2006-07-28       Impact factor: 13.382

6.  Reversal of phencyclidine effects by a group II metabotropic glutamate receptor agonist in rats.

Authors:  B Moghaddam; B W Adams
Journal:  Science       Date:  1998-08-28       Impact factor: 47.728

Review 7.  Recent progress on the identification of metabotropic glutamate 4 receptor ligands and their potential utility as CNS therapeutics.

Authors:  Albert J Robichaud; Darren W Engers; Craig W Lindsley; Corey R Hopkins
Journal:  ACS Chem Neurosci       Date:  2011-06-14       Impact factor: 4.418

8.  Targeting group II metabotropic glutamate (mGlu) receptors for the treatment of psychosis associated with Alzheimer's disease: selective activation of mGlu2 receptors amplifies beta-amyloid toxicity in cultured neurons, whereas dual activation of mGlu2 and mGlu3 receptors is neuroprotective.

Authors:  Filippo Caraci; Gemma Molinaro; Giuseppe Battaglia; Maria Laura Giuffrida; Barbara Riozzi; Anna Traficante; Valeria Bruno; Milena Cannella; Sara Merlo; Xushan Wang; Beverly A Heinz; Eric S Nisenbaum; Thomas C Britton; Filippo Drago; Maria Angela Sortino; Agata Copani; Ferdinando Nicoletti
Journal:  Mol Pharmacol       Date:  2010-12-15       Impact factor: 4.436

9.  Discovery of molecular switches that modulate modes of metabotropic glutamate receptor subtype 5 (mGlu5) pharmacology in vitro and in vivo within a series of functionalized, regioisomeric 2- and 5-(phenylethynyl)pyrimidines.

Authors:  Sameer Sharma; Jeffrey Kedrowski; Jerri M Rook; Randy L Smith; Carrie K Jones; Alice L Rodriguez; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2009-07-23       Impact factor: 7.446

Review 10.  Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders.

Authors:  P Jeffrey Conn; Arthur Christopoulos; Craig W Lindsley
Journal:  Nat Rev Drug Discov       Date:  2009-01       Impact factor: 84.694
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  20 in total

Review 1.  Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Authors:  Craig W Lindsley; Kyle A Emmitte; Corey R Hopkins; Thomas M Bridges; Karen J Gregory; Colleen M Niswender; P Jeffrey Conn
Journal:  Chem Rev       Date:  2016-02-16       Impact factor: 60.622

2.  Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation.

Authors:  Karen J Gregory; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2015-03-25       Impact factor: 4.436

3.  Further optimization of the mGlu5 PAM clinical candidate VU0409551/JNJ-46778212: Progress and challenges towards a back-up compound.

Authors:  Ya Zhou; Chrysa Malosh; Susana Conde-Ceide; Carlos Manuel Martínez-Viturro; Jesus Alcázar; Hilde Lavreysen; Claire Mackie; Thomas M Bridges; J Scott Daniels; Colleen M Niswender; Carrie K Jones; Gregor J Macdonald; Thomas Steckler; P Jeffrey Conn; Shaun R Stauffer; José Manuel Bartolomé-Nebreda; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2015-07-04       Impact factor: 2.823

4.  Probing the metabotropic glutamate receptor 5 (mGlu₅) positive allosteric modulator (PAM) binding pocket: discovery of point mutations that engender a "molecular switch" in PAM pharmacology.

Authors:  Karen J Gregory; Elizabeth D Nguyen; Sean D Reiff; Emma F Squire; Shaun R Stauffer; Craig W Lindsley; Jens Meiler; P Jeffrey Conn
Journal:  Mol Pharmacol       Date:  2013-02-26       Impact factor: 4.436

Review 5.  Drugs for allosteric sites on receptors.

Authors:  Cody J Wenthur; Patrick R Gentry; Thomas P Mathews; Craig W Lindsley
Journal:  Annu Rev Pharmacol Toxicol       Date:  2013-10-02       Impact factor: 13.820

6.  Identification of specific ligand-receptor interactions that govern binding and cooperativity of diverse modulators to a common metabotropic glutamate receptor 5 allosteric site.

Authors:  Karen J Gregory; Elizabeth D Nguyen; Chrysa Malosh; Jeffrey L Mendenhall; Jessica Z Zic; Brittney S Bates; Meredith J Noetzel; Emma F Squire; Eric M Turner; Jerri M Rook; Kyle A Emmitte; Shaun R Stauffer; Craig W Lindsley; Jens Meiler; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2014-02-26       Impact factor: 4.418

Review 7.  Progress toward advanced understanding of metabotropic glutamate receptors: structure, signaling and therapeutic indications.

Authors:  Shen Yin; Colleen M Niswender
Journal:  Cell Signal       Date:  2014-05-02       Impact factor: 4.315

8.  Design and Synthesis of N-Aryl Phenoxyethoxy Pyridinones as Highly Selective and CNS Penetrant mGlu3 NAMs.

Authors:  Julie L Engers; Katrina A Bollinger; Rebecca L Weiner; Alice L Rodriguez; Madeline F Long; Megan M Breiner; Sichen Chang; Sean R Bollinger; Michael Bubser; Carrie K Jones; Ryan D Morrison; Thomas M Bridges; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Kyle A Emmitte; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2017-08-15       Impact factor: 4.345

Review 9.  Allosteric modulation of Class C GPCRs: a novel approach for the treatment of CNS disorders.

Authors:  Darren W Engers; Craig W Lindsley
Journal:  Drug Discov Today Technol       Date:  2013

10.  Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM).

Authors:  Cody J Wenthur; Ryan Morrison; Andrew S Felts; Katrina A Smith; Julie L Engers; Frank W Byers; J Scott Daniels; Kyle A Emmitte; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2013-06-13       Impact factor: 7.446
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