Literature DB >> 23562060

Discovery of ML326: The first sub-micromolar, selective M5 PAM.

Patrick R Gentry1, Thomas M Bridges, Atin Lamsal, Paige N Vinson, Emery Smith, Peter Chase, Peter S Hodder, Julie L Engers, Colleen M Niswender, J Scott Daniels, P Jeffrey Conn, Michael R Wood, Craig W Lindsley.   

Abstract

This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409nM and 500nM, respectively) with excellent mAChR selectivity (M1-M4 EC50s >30μM) and a robust 20-fold leftward shift of the ACh CRC.
Copyright © 2013 Elsevier Ltd. All rights reserved.

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Year:  2013        PMID： 23562060      PMCID： PMC3634896          DOI： 10.1016/j.bmcl.2013.03.032

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


  21 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.  Facile synthesis of azaarene-substituted 3-hydroxy-2-oxindoles via Brønsted acid catalyzed sp3 C-H functionalization.

Authors:  Rui Niu; Jian Xiao; Tao Liang; Xingwei Li
Journal:  Org Lett       Date:  2012-01-24       Impact factor: 6.005

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

4.  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

5.  Identification of a family of muscarinic acetylcholine receptor genes.

Authors:  T I Bonner; N J Buckley; A C Young; M R Brann
Journal:  Science       Date:  1987-07-31       Impact factor: 47.728

6.  Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM.

Authors:  Thomas M Bridges; J Phillip Kennedy; Meredith J Noetzel; Micah L Breininger; Patrick R Gentry; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2010-02-01       Impact factor: 2.823

Review 7.  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

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.  Decreased prepulse inhibition and increased sensitivity to muscarinic, but not dopaminergic drugs in M5 muscarinic acetylcholine receptor knockout mice.

Authors:  Morgane Thomsen; Gitta Wörtwein; Anders Fink-Jensen; David P D Woldbye; Jürgen Wess; S Barak Caine
Journal:  Psychopharmacology (Berl)       Date:  2007-02-20       Impact factor: 4.415

10.  Variation in the gene coding for the M5 muscarinic receptor (CHRM5) influences cigarette dose but is not associated with dependence to drugs of addiction: evidence from a prospective population based cohort study of young adults.

Authors:  Richard J L Anney; Mehrnoush Lotfi-Miri; Craig A Olsson; Sophie C Reid; Sheryl A Hemphill; George C Patton
Journal:  BMC Genet       Date:  2007-07-03       Impact factor: 2.797
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  10 in total

Review 1.  Advancing Biological Understanding and Therapeutics Discovery with Small-Molecule Probes.

Authors:  Stuart L Schreiber; Joanne D Kotz; Min Li; Jeffrey Aubé; Christopher P Austin; John C Reed; Hugh Rosen; E Lucile White; Larry A Sklar; Craig W Lindsley; Benjamin R Alexander; Joshua A Bittker; Paul A Clemons; Andrea de Souza; Michael A Foley; Michelle Palmer; Alykhan F Shamji; Mathias J Wawer; Owen McManus; Meng Wu; Beiyan Zou; Haibo Yu; Jennifer E Golden; Frank J Schoenen; Anton Simeonov; Ajit Jadhav; Michael R Jackson; Anthony B Pinkerton; Thomas D Y Chung; Patrick R Griffin; Benjamin F Cravatt; Peter S Hodder; William R Roush; Edward Roberts; Dong-Hoon Chung; Colleen B Jonsson; James W Noah; William E Severson; Subramaniam Ananthan; Bruce Edwards; Tudor I Oprea; P Jeffrey Conn; Corey R Hopkins; Michael R Wood; Shaun R Stauffer; Kyle A Emmitte
Journal:  Cell       Date:  2015-06-04       Impact factor: 41.582

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.  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

4.  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

5.  Chronic loss of muscarinic M5 receptor function manifests disparate impairments in exploratory behavior in male and female mice despite common dopamine regulation.

Authors:  John A Razidlo; Skylar M L Fausner; Anna E Ingebretson; Liuchang C Wang; Christopher M Petersen; Salahudeen Mirza; Isabella N Swank; Veronica A Alvarez; Julia C Lemos
Journal:  J Neurosci       Date:  2022-07-26       Impact factor: 6.709

6.  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

7.  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 8.  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

9.  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

Review 10.  Multitargeting nature of muscarinic orthosteric agonists and antagonists.

Authors:  Jaromir Myslivecek
Journal:  Front Physiol       Date:  2022-09-06       Impact factor: 4.755
  10 in total

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