Literature DB >> 29678111

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

Aaron M Bender, Hyekyung P Cho, Kellie D Nance, Kaelyn S Lingenfelter, Vincent B Luscombe, Patrick R Gentry, Karl Voigtritter, Alice E Berizzi1, Patrick M Sexton1, Christopher J Langmead1, Arthur Christopoulos1, 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.   

Abstract

The pharmacology of the M5 muscarinic acetylcholine receptor (mAChR) is the least understood of the five mAChR subtypes due to a historic lack of selective small molecule tools. To address this shortcoming, we have continued the optimization effort around the prototypical M5 positive allosteric modulator (PAM) ML380 and have discovered and optimized a new series of M5 PAMs based on a chiral N-(indanyl)piperidine amide core with robust SAR, human and rat M5 PAM EC50 values <100 nM and rat brain/plasma Kp values of ∼0.40. Interestingly, unlike M1 and M4 PAMs with unprecedented mAChR subtype selectivity, this series of M5 PAMs displayed varying degrees of PAM activity at the other two natively Gq-coupled mAChRs, M1 and M3, yet were inactive at M2 and M4.

Entities:  

Keywords:  M5; SAR; muscarinic acetylcholine receptor; positive allosteric modulator (PAM); selectivity

Mesh：

Substances：

Year:  2018        PMID： 29678111      PMCID： PMC6104635          DOI： 10.1021/acschemneuro.8b00126

Source DB:  PubMed          Journal:  ACS Chem Neurosci        ISSN： 1948-7193            Impact factor:   4.418


  33 in total

1.  Identification and localization of muscarinic acetylcholine receptor proteins in brain with subtype-specific antibodies.

Authors:  A I Levey; C A Kitt; W F Simonds; D L Price; M R Brann
Journal:  J Neurosci       Date:  1991-10       Impact factor: 6.167

2.  Expression of m1-m4 muscarinic acetylcholine receptor proteins in rat hippocampus and regulation by cholinergic innervation.

Authors:  A I Levey; S M Edmunds; V Koliatsos; R G Wiley; C J Heilman
Journal:  J Neurosci       Date:  1995-05       Impact factor: 6.167

3.  Biotransformation of a novel positive allosteric modulator of metabotropic glutamate receptor subtype 5 contributes to seizure-like adverse events in rats involving a receptor agonism-dependent mechanism.

Authors:  Thomas M Bridges; Jerri M Rook; Meredith J Noetzel; Ryan D Morrison; Ya Zhou; Rocco D Gogliotti; Paige N Vinson; Zixiu Xiang; Carrie K Jones; Colleen M Niswender; Craig W Lindsley; Shaun R Stauffer; P Jeffrey Conn; J Scott Daniels
Journal:  Drug Metab Dispos       Date:  2013-07-02       Impact factor: 3.922

Review 4.  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

5.  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 6.  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

Review 7.  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

8.  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).

Authors:  Patrick R Gentry; 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
Journal:  J Med Chem       Date:  2013-11-13       Impact factor: 7.446

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

10.  Development of a highly potent, novel M5 positive allosteric modulator (PAM) demonstrating CNS exposure: 1-((1H-indazol-5-yl)sulfoneyl)-N-ethyl-N-(2-(trifluoromethyl)benzyl)piperidine-4-carboxamide (ML380).

Authors:  Patrick R Gentry; Masaya Kokubo; Thomas M Bridges; Meredith J Noetzel; Hyekyung P Cho; Atin Lamsal; Emery Smith; Peter Chase; Peter S Hodder; Colleen M Niswender; J Scott Daniels; P Jeffrey Conn; Craig W Lindsley; Michael R Wood
Journal:  J Med Chem       Date:  2014-09-03       Impact factor: 7.446
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  3 in total

Review 1.  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

2.  Discovery and Optimization of a Novel Series of Competitive and Central Nervous System-Penetrant Protease-Activated Receptor 4 (PAR4) Inhibitors.

Authors:  Jeanette L Bertron; Matthew T Duvernay; Sidnee G Mitchell; Shannon T Smith; Jae G Maeng; Anna L Blobaum; Dexter C Davis; Jens Meiler; Heidi E Hamm; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2021-12-02       Impact factor: 4.418

Review 3.  Targeting muscarinic receptors to treat schizophrenia.

Authors:  Daniel J Foster; Zoey K Bryant; P Jeffrey Conn
Journal:  Behav Brain Res       Date:  2021-02-26       Impact factor: 3.332
  3 in total

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