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Literature DB >> 29057060

Discovery of VU6005649, a CNS Penetrant mGlu_7/8 Receptor PAM Derived from a Series of Pyrazolo[1,5-a]pyrimidines.

Masahito Abe^1,2, Mabel Seto^1,2, Rocco G Gogliotti^1,2, Matthew T Loch^1,2, Katrina A Bollinger², Sichen Chang², Eileen M Engelberg^1,2, Vincent B Luscombe^1,2, Joel M Harp³, Michael Bubser^1,2, Darren W Engers^1,2, Carrie K Jones^1,2,4, Alice L Rodriguez^1,2, Anna L Blobaum^1,2, P Jeffrey Conn^1,2,4, Colleen M Niswender^1,2,4, Craig W Lindsley^1,2,4.

Abstract

Herein, we report the structure-activity relationships within a series of mGlu7 PAMs based on a pyrazolo[1,5-a]pyrimidine core with excellent CNS penetration (Kps > 1 and Kp,uus > 1). Analogues in this series proved to display a range of Group III mGlu receptor selectivity, but VU6005649 emerged as the first dual mGlu7/8 PAM, filling a void in the Group III mGlu receptor PAM toolbox and demonstrating in vivo efficacy in a mouse contextual fear conditioning model.

Entities: Chemical Species

Keywords: Positive allosteric modulator (PAM); Rett syndrome; VU6005649; cognition; metabotropic glutamate receptor 7 (mGlu7)

Year: 2017 PMID： 29057060 PMCID： PMC5641958 DOI： 10.1021/acsmedchemlett.7b00317

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

30 in total

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2. A potent and selective metabotropic glutamate receptor 4 positive allosteric modulator improves movement in rodent models of Parkinson's disease.

Authors: Emmanuel Le Poul; Christelle Boléa; Francoise Girard; Sonia Poli; Delphine Charvin; Brice Campo; Julien Bortoli; Abdhelak Bessif; Bin Luo; Amy Jo Koser; Lisa M Hodge; Karen M Smith; Anthony G DiLella; Nigel Liverton; Fred Hess; Susan E Browne; Ian J Reynolds
Journal: J Pharmacol Exp Ther Date: 2012-07-11 Impact factor: 4.030

Review 3. 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

4. Deficits in acquisition and extinction of conditioned responses in mGluR7 knockout mice.

Authors: Hannelore Goddyn; Zsuzsanna Callaerts-Vegh; Stijn Stroobants; Trinette Dirikx; Debora Vansteenwegen; Dirk Hermans; Herman van der Putten; Rudi D'Hooge
Journal: Neurobiol Learn Mem Date: 2008-03-04 Impact factor: 2.877

5. Significant association of GRM7 and GRM8 genes with schizophrenia and major depressive disorder in the Han Chinese population.

Authors: Wenjin Li; Kang Ju; Zhiqiang Li; Kuanjun He; Jianhua Chen; Qingzhong Wang; Beimeng Yang; Lin An; Guoyin Feng; Weiming Sun; Juan Zhou; Shasha Zhang; Pingping Song; Raja Amjad Waheed Khan; Weidong Ji; Yongyong Shi
Journal: Eur Neuropsychopharmacol Date: 2015-05-27 Impact factor: 4.600

6. High-resolution chromosome ideogram representation of recognized genes for bipolar disorder.

Authors: Lindsay N Douglas; Austen B McGuire; Ann M Manzardo; Merlin G Butler
Journal: Gene Date: 2016-04-07 Impact factor: 3.688

7. Altered short-term synaptic plasticity in mice lacking the metabotropic glutamate receptor mGlu7.

Authors: Trevor J Bushell; Gilles Sansig; Valerie J Collett; Herman van der Putten; Graham L Collingridge
Journal: ScientificWorldJournal Date: 2002-03-15

8. Novel loci for major depression identified by genome-wide association study of Sequenced Treatment Alternatives to Relieve Depression and meta-analysis of three studies.

Authors: S I Shyn; J Shi; J B Kraft; J B Potash; J A Knowles; M M Weissman; H A Garriock; J S Yokoyama; P J McGrath; E J Peters; W A Scheftner; W Coryell; W B Lawson; D Jancic; P V Gejman; A R Sanders; P Holmans; S L Slager; D F Levinson; S P Hamilton
Journal: Mol Psychiatry Date: 2009-12-29 Impact factor: 15.992

9. Identification of positive allosteric modulators VU0155094 (ML397) and VU0422288 (ML396) reveals new insights into the biology of metabotropic glutamate receptor 7.

Authors: Nidhi Jalan-Sakrikar; Julie R Field; Rebecca Klar; Margrith E Mattmann; Karen J Gregory; Rocio Zamorano; Darren W Engers; Sean R Bollinger; C David Weaver; Emily L Days; L Michelle Lewis; Thomas J Utley; Miguel Hurtado; Delphine Rigault; Francine Acher; Adam G Walker; Bruce J Melancon; Michael R Wood; Craig W Lindsley; P Jeffrey Conn; Zixiu Xiang; Corey R Hopkins; Colleen M Niswender
Journal: ACS Chem Neurosci Date: 2014-10-09 Impact factor: 4.418

10. Allelic association, DNA resequencing and copy number variation at the metabotropic glutamate receptor GRM7 gene locus in bipolar disorder.

Authors: Radhika Kandaswamy; Andrew McQuillin; David Curtis; Hugh Gurling
Journal: Am J Med Genet B Neuropsychiatr Genet Date: 2014-05-08 Impact factor: 3.568

7 in total

1. Discovery of VU6027459: A First-in-Class Selective and CNS Penetrant mGlu₇ Positive Allosteric Modulator Tool Compound.

Authors: Carson W Reed; Jacob J Kalbfleisch; Madison J Wong; Jordan P Washecheck; Ashton Hunter; Alice L Rodriguez; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley
Journal: ACS Med Chem Lett Date: 2020-08-20 Impact factor: 4.345

2. VU6010608, a Novel mGlu₇ NAM from a Series of N-(2-(1H-1,2,4-Triazol-1-yl)-5-(trifluoromethoxy)phenyl)benzamides.

Authors: Carson W Reed; Kevin M McGowan; Paul K Spearing; Branden J Stansley; Hanna F Roenfanz; Darren W Engers; Alice L Rodriguez; Eileen M Engelberg; Vincent B Luscombe; Matthew T Loch; Daniel H Remke; Jerri M Rook; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley
Journal: ACS Med Chem Lett Date: 2017-11-08 Impact factor: 4.345

3. Synthesis and SAR of a series of mGlu₇ NAMs based on an ethyl-8-methoxy-4-(4-phenylpiperazin-1-yl)quinoline carboxylate core.

Authors: Jacob J Kalbfleisch; Carson W Reed; Charlotte Park; Paul K Spearing; Marc C Quitalig; Matthew T Jenkins; Alice L Rodriguez; Anna L Blobaum; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley
Journal: Bioorg Med Chem Lett Date: 2020-09-02 Impact factor: 2.823

Review 7. Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold.

Authors: Andres Arias-Gómez; Andrés Godoy; Jaime Portilla
Journal: Molecules Date: 2021-05-05 Impact factor: 4.411