Literature DB >> 24164599

Discovery of the first M5-selective and CNS penetrant negative allosteric modulator (NAM) of a muscarinic acetylcholine receptor: (S)-9b-(4-chlorophenyl)-1-(3,4-difluorobenzoyl)-2,3-dihydro-1H-imidazo[2,1-a]isoindol-5(9bH)-one (ML375).

Patrick R Gentry1, Masaya Kokubo, Thomas M Bridges, Nathan R Kett, Joel M Harp, Hyekyung P Cho, Emery Smith, Peter Chase, Peter S Hodder, Colleen M Niswender, J Scott Daniels, P Jeffrey Conn, Michael R Wood, Craig W Lindsley.   

Abstract

A functional high throughput screen and subsequent multidimensional, iterative parallel synthesis effort identified the first muscarinic acetylcholine receptor (mAChR) negative allosteric modulator (NAM) selective for the M5 subtype. ML375 is a highly selective M5 NAM with submicromolar potency (human M5 IC50 = 300 nM, rat M5 IC50 = 790 nM, M1-M4 IC50 > 30 μM), excellent multispecies PK, high CNS penetration, and enantiospecific inhibition.

Entities:  

Mesh：

Substances：

Year:  2013        PMID： 24164599      PMCID： PMC3876027          DOI： 10.1021/jm4013246

Source DB:  PubMed          Journal:  J Med Chem        ISSN： 0022-2623            Impact factor:   7.446


  19 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

Review 2.  Section I. The cholinergic system.

Authors:  John Smythies
Journal:  Int Rev Neurobiol       Date:  2005       Impact factor: 3.230

3.  Expression of muscarinic acetylcholine and dopamine receptor mRNAs in rat basal ganglia.

Authors:  D M Weiner; A I Levey; M R Brann
Journal:  Proc Natl Acad Sci U S A       Date:  1990-09       Impact factor: 11.205

Review 4.  International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors.

Authors:  M P Caulfield; N J Birdsall
Journal:  Pharmacol Rev       Date:  1998-06       Impact factor: 25.468

5.  Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse and Parkinson's Disease.

Authors:  Ditte Dencker; Morgane Thomsen; Gitta Wörtwein; Pia Weikop; Yinghong Cui; Jongrye Jeon; Jürgen Wess; Anders Fink-Jensen
Journal:  ACS Chem Neurosci       Date:  2012       Impact factor: 4.418

Review 6.  Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development.

Authors:  Jürgen Wess; Richard M Eglen; Dinesh Gautam
Journal:  Nat Rev Drug Discov       Date:  2007-09       Impact factor: 84.694

7.  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

Review 8.  Subtype-selective allosteric modulators of muscarinic receptors for the treatment of CNS disorders.

Authors:  P Jeffrey Conn; Carrie K Jones; Craig W Lindsley
Journal:  Trends Pharmacol Sci       Date:  2009-02-07       Impact factor: 14.819

9.  Targeting selective activation of M(1) for the treatment of Alzheimer's disease: further chemical optimization and pharmacological characterization of the M(1) positive allosteric modulator ML169.

Authors:  James C Tarr; Mark L Turlington; Paul R Reid; Thomas J Utley; Douglas J Sheffler; Hyekyung P Cho; Rebecca Klar; Tristano Pancani; Michael T Klein; Thomas M Bridges; Ryan D Morrison; Anna L Blobaum; Zixui Xiang; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Michael R Wood; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2012-07-18       Impact factor: 4.418

Review 10.  Muscarinic acetylcholine receptors as CNS drug targets.

Authors:  Christopher J Langmead; Jeannette Watson; Charlie Reavill
Journal:  Pharmacol Ther       Date:  2007-12-20       Impact factor: 12.310
View more
  17 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

Review 2.  Current approaches for the discovery of drugs that deter substance and drug abuse.

Authors:  Adam Yasgar; Anton Simeonov
Journal:  Expert Opin Drug Discov       Date:  2014-09-24       Impact factor: 6.098

3.  Prediction of consensus binding mode geometries for related chemical series of positive allosteric modulators of adenosine and muscarinic acetylcholine receptors.

Authors:  Leon A Sakkal; Kyle Z Rajkowski; Roger S Armen
Journal:  J Comput Chem       Date:  2017-01-28       Impact factor: 3.376

4.  Discovery and Optimization of Potent and CNS Penetrant M5-Preferring Positive Allosteric Modulators Derived from a Novel, Chiral N-(Indanyl)piperidine Amide Scaffold.

Authors:  Aaron M Bender; Hyekyung P Cho; Kellie D Nance; Kaelyn S Lingenfelter; Vincent B Luscombe; Patrick R Gentry; Karl Voigtritter; Alice E Berizzi; Patrick M Sexton; Christopher J Langmead; Arthur Christopoulos; Charles W Locuson; Thomas M Bridges; Sichen Chang; Jordan C O'Neill; Xiaoyan Zhan; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2018-04-26       Impact factor: 4.418

5.  Selective inhibition of M5 muscarinic acetylcholine receptors attenuates cocaine self-administration in rats.

Authors:  Barak W Gunter; Robert W Gould; Michael Bubser; Kevin M McGowan; Craig W Lindsley; Carrie K Jones
Journal:  Addict Biol       Date:  2017-10-18       Impact factor: 4.280

6.  Further optimization of the M5 NAM MLPCN probe ML375: tactics and challenges.

Authors:  Haruto Kurata; Patrick R Gentry; Masaya Kokubo; Hyekyung P Cho; Thomas M Bridges; Colleen M Niswender; Frank W Byers; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2014-12-13       Impact factor: 2.823

Review 7.  Acyclic Twisted Amides.

Authors:  Guangrong Meng; Jin Zhang; Michal Szostak
Journal:  Chem Rev       Date:  2021-08-18       Impact factor: 72.087

Review 8.  Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders.

Authors:  Sean P Moran; James Maksymetz; P Jeffrey Conn
Journal:  Trends Pharmacol Sci       Date:  2019-11-08       Impact factor: 14.819

9.  Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe.

Authors:  Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Hyekyung P Cho; Emery Smith; Peter Chase; Peter S Hodder; Thomas J Utley; Anuruddha Rajapakse; Frank Byers; Colleen M Niswender; Ryan D Morrison; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley
Journal:  ChemMedChem       Date:  2014-04-01       Impact factor: 3.466

Review 10.  Allosteric Modulation of Class A GPCRs: Targets, Agents, and Emerging Concepts.

Authors:  Eric A Wold; Jianping Chen; Kathryn A Cunningham; Jia Zhou
Journal:  J Med Chem       Date:  2018-08-28       Impact factor: 7.446
View more

北京卡尤迪生物科技股份有限公司 © 2022-2023.