Literature DB >> 28947937

Design and Synthesis of mGlu2 NAMs with Improved Potency and CNS Penetration Based on a Truncated Picolinamide Core.

Katrina A Bollinger1, Andrew S Felts2,1, Christopher J Brassard2,1, Julie L Engers2,1, Alice L Rodriguez2,1, Rebecca L Weiner1, Hyekyung P Cho2,1, Sichen Chang1, Michael Bubser2,1, Carrie K Jones2,1,3, Anna L Blobaum2,1, Colleen M Niswender2,1,3, P Jeffrey Conn2,1,3, Kyle A Emmitte2,1,4, Craig W Lindsley2,1,4.   

Abstract

Herein, we detail the optimization of the mGlu2 negative allosteric modulator (NAM), VU6001192, by a reductionist approach to afford a novel, simplified mGlu2 NAM scaffold. This new chemotype not only affords potent and selective mGlu2 inhibition, as exemplified by VU6001966 (mGlu2 IC50 = 78 nM, mGlu3 IC50 > 30 μM), but also excellent central nervous system (CNS) penetration (Kp = 1.9, Kp,uu = 0.78), a feature devoid in all previously disclosed mGlu2 NAMs (Kps ≈ 0.3, Kp,uus ≈ 0.1). Moreover, this series, based on overall properties, represents an exciting lead series for potential mGlu2 PET tracer development.

Entities:  

Keywords:  CNS penetration; Negative allosteric modulator (NAM); VU6001966; depression; metabotropic glutamate receptor 2 (mGlu2)

Year:  2017        PMID： 28947937      PMCID： PMC5601377          DOI： 10.1021/acsmedchemlett.7b00279

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  20 in total

1.  Distribution of a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat and mouse: an immunohistochemical study with a monoclonal antibody.

Authors:  H Ohishi; A Neki; N Mizuno
Journal:  Neurosci Res       Date:  1998-01       Impact factor: 3.304

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

Authors:  Douglas J Sheffler; 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
Journal:  Bioorg Med Chem Lett       Date:  2012-04-30       Impact factor: 2.823

3.  Distribution of the messenger RNA for a metabotropic glutamate receptor, mGluR2, in the central nervous system of the rat.

Authors:  H Ohishi; R Shigemoto; S Nakanishi; N Mizuno
Journal:  Neuroscience       Date:  1993-04       Impact factor: 3.590

4.  Immunohistochemical localization of metabotropic glutamate receptors, mGluR2 and mGluR3, in rat cerebellar cortex.

Authors:  H Ohishi; R Ogawa-Meguro; R Shigemoto; T Kaneko; S Nakanishi; N Mizuno
Journal:  Neuron       Date:  1994-07       Impact factor: 17.173

5.  Distribution and abundance of metabotropic glutamate receptor subtype 2 in rat brain revealed by [3H]LY354740 binding in vitro and quantitative radioautography: correlation with the sites of synthesis, expression, and agonist stimulation of [35S]GTPgammas binding.

Authors:  Grayson Richards; Jürg Messer; Pari Malherbe; Richard Pink; Manfred Brockhaus; Heinz Stadler; Jürgen Wichmann; Hervé Schaffhauser; Vincent Mutel
Journal:  J Comp Neurol       Date:  2005-06-20       Impact factor: 3.215

Review 6.  Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system.

Authors:  D D Schoepp
Journal:  J Pharmacol Exp Ther       Date:  2001-10       Impact factor: 4.030

7.  Immunohistochemical localization of metabotropic glutamate receptors mGluR1a and mGluR2/3 in the rat basal ganglia.

Authors:  C M Testa; I K Friberg; S W Weiss; D G Standaert
Journal:  J Comp Neurol       Date:  1998-01-05       Impact factor: 3.215

Review 8.  Metabotropic glutamate receptors: physiology, pharmacology, and disease.

Authors:  Colleen M Niswender; P Jeffrey Conn
Journal:  Annu Rev Pharmacol Toxicol       Date:  2010       Impact factor: 13.820

9.  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

10.  Metabotropic glutamate receptor II in the brains of Parkinsonian patients.

Authors:  Pershia Samadi; Alex Rajput; Frédéric Calon; Laurent Grégoire; Oleh Hornykiewicz; Ali H Rajput; Thèrèse Di Paolo
Journal:  J Neuropathol Exp Neurol       Date:  2009-04       Impact factor: 3.685
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  11 in total

1.  mGlu2 and mGlu3 Negative Allosteric Modulators Divergently Enhance Thalamocortical Transmission and Exert Rapid Antidepressant-like Effects.

Authors:  Max E Joffe; Chiaki I Santiago; Kendra H Oliver; James Maksymetz; Nicholas A Harris; Julie L Engers; Craig W Lindsley; Danny G Winder; P Jeffrey Conn
Journal:  Neuron       Date:  2019-11-14       Impact factor: 17.173

Review 2.  The neurobiological basis for novel experimental therapeutics in dystonia.

Authors:  Anthony M Downs; Kaitlyn M Roman; Simone A Campbell; Antonio Pisani; Ellen J Hess; Paola Bonsi
Journal:  Neurobiol Dis       Date:  2019-07-04       Impact factor: 5.996

3.  Amygdala group II mGluRs mediate the inhibitory effects of systemic group II mGluR activation on behavior and spinal neurons in a rat model of arthritis pain.

Authors:  Mariacristina Mazzitelli; Volker Neugebauer
Journal:  Neuropharmacology       Date:  2019-07-12       Impact factor: 5.250

4.  Synthesis and Characterization of 5-(2-Fluoro-4-[11C]methoxyphenyl)-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3-b]pyridine-7-carboxamide as a PET Imaging Ligand for Metabotropic Glutamate Receptor 2.

Authors:  Gengyang Yuan; Maeva Dhaynaut; Yu Lan; Nicolas J Guehl; Dalena Huynh; Suhasini M Iyengar; Sepideh Afshar; Manish Kumar Jain; Julie E Pickett; Hye Jin Kang; Hao Wang; Sung-Hyun Moon; Mary Jo Ondrechen; Changning Wang; Timothy M Shoup; Georges El Fakhri; Marc D Normandin; Anna-Liisa Brownell
Journal:  J Med Chem       Date:  2022-01-28       Impact factor: 8.039

5.  Functional partnership between mGlu3 and mGlu5 metabotropic glutamate receptors in the central nervous system.

Authors:  Luisa Di Menna; Max E Joffe; Luisa Iacovelli; Rosamaria Orlando; Craig W Lindsley; Jèrome Mairesse; Pierre Gressèns; Milena Cannella; Filippo Caraci; Agata Copani; Valeria Bruno; Giuseppe Battaglia; P Jeffrey Conn; Ferdinando Nicoletti
Journal:  Neuropharmacology       Date:  2017-10-25       Impact factor: 5.250

6.  G-protein activation by a metabotropic glutamate receptor.

Authors:  Alpay B Seven; Ximena Barros-Álvarez; Marine de Lapeyrière; Makaía M Papasergi-Scott; Michael J Robertson; Chensong Zhang; Robert M Nwokonko; Yang Gao; Justin G Meyerowitz; Jean-Philippe Rocher; Dominik Schelshorn; Brian K Kobilka; Jesper M Mathiesen; Georgios Skiniotis
Journal:  Nature       Date:  2021-06-30       Impact factor: 69.504

7.  Activating mGlu3 Metabotropic Glutamate Receptors Rescues Schizophrenia-like Cognitive Deficits Through Metaplastic Adaptations Within the Hippocampus.

Authors:  Shalini Dogra; Branden J Stansley; Zixiu Xiang; Weilun Qian; Rocco G Gogliotti; Ferdinando Nicoletti; Craig W Lindsley; Colleen M Niswender; Max E Joffe; P Jeffrey Conn
Journal:  Biol Psychiatry       Date:  2021-03-06       Impact factor: 12.810

8.  Classification models and SAR analysis on CysLT1 receptor antagonists using machine learning algorithms.

Authors:  Hongzhao Wang; Zijian Qin; Aixia Yan
Journal:  Mol Divers       Date:  2021-02-03       Impact factor: 3.364

Review 9.  Group II Metabotropic Glutamate Receptors: Role in Pain Mechanisms and Pain Modulation.

Authors:  Mariacristina Mazzitelli; Enza Palazzo; Sabatino Maione; Volker Neugebauer
Journal:  Front Mol Neurosci       Date:  2018-10-09       Impact factor: 5.639

10.  Profiling the Structural Determinants of Aryl Benzamide Derivatives as Negative Allosteric Modulators of mGluR5 by In Silico Study.

Authors:  Yujing Zhao; Jiabin Chen; Qilei Liu; Yan Li
Journal:  Molecules       Date:  2020-01-18       Impact factor: 4.411
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