Literature DB >> 21194936

Discovery and optimization of a novel, selective and brain penetrant M1 positive allosteric modulator (PAM): the development of ML169, an MLPCN probe.

Paul R Reid1, Thomas M Bridges, Douglas J Sheffler, Hyekyung P Cho, L Michelle Lewis, Emily Days, J Scott Daniels, Carrie K Jones, Colleen M Niswender, C David Weaver, P Jeffrey Conn, Craig W Lindsley, Michael R Wood.   

Abstract

This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M(1) PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M(1) PAM with an in vitro profile comparable to the prototypical M(1) PAM, BQCA, but with an improved brain to plasma ratio.
Copyright © 2010 Elsevier Ltd. All rights reserved.

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Year:  2010        PMID： 21194936      PMCID： PMC3082000          DOI： 10.1016/j.bmcl.2010.12.015

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


  20 in total

1.  Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous system.

Authors:  Evan P Lebois; Thomas M Bridges; L Michelle Lewis; Eric S Dawson; Alexander S Kane; Zixiu Xiang; Satyawan B Jadhav; Huiyong Yin; J Phillip Kennedy; Jens Meiler; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; C David Weaver; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2010       Impact factor: 4.418

Review 2.  Allosteric modulation of kinases and GPCRs: design principles and structural diversity.

Authors:  Jana A Lewis; Evan P Lebois; Craig W Lindsley
Journal:  Curr Opin Chem Biol       Date:  2008-04-18       Impact factor: 8.822

3.  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

4.  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

5.  A selective allosteric potentiator of the M1 muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning.

Authors:  Jana K Shirey; Ashley E Brady; Paulianda J Jones; Albert A Davis; Thomas M Bridges; J Phillip Kennedy; Satyawan B Jadhav; Usha N Menon; Zixiu Xiang; Mona L Watson; Edward P Christian; James J Doherty; Michael C Quirk; Dean H Snyder; James J Lah; Allan I Levey; Michelle M Nicolle; Craig W Lindsley; P Jeffrey Conn
Journal:  J Neurosci       Date:  2009-11-11       Impact factor: 6.167

6.  Selective activation of the M1 muscarinic acetylcholine receptor achieved by allosteric potentiation.

Authors:  Lei Ma; Matthew A Seager; Matthew Seager; Marion Wittmann; Marlene Jacobson; Denise Bickel; Maryann Burno; Keith Jones; Valerie Kuzmick Graufelds; Guangping Xu; Michelle Pearson; Alexander McCampbell; Renee Gaspar; Paul Shughrue; Andrew Danziger; Christopher Regan; Rose Flick; Danette Pascarella; Susan Garson; Scott Doran; Constantine Kreatsoulas; Lone Veng; Craig W Lindsley; William Shipe; Scott Kuduk; Cyrille Sur; Gene Kinney; Guy R Seabrook; William J Ray
Journal:  Proc Natl Acad Sci U S A       Date:  2009-08-26       Impact factor: 11.205

Review 7.  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 8.  Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications.

Authors:  Jürgen Wess
Journal:  Annu Rev Pharmacol Toxicol       Date:  2004       Impact factor: 13.820

Review 9.  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

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
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  31 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.  Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071.

Authors:  Evan P Lebois; Gregory J Digby; Douglas J Sheffler; Bruce J Melancon; James C Tarr; Hyekyung P Cho; Nicole R Miller; Ryan Morrison; Thomas M Bridges; Zixiu Xiang; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2011-08-24       Impact factor: 2.823

3.  Application of Parallel Multiparametric Cell-Based FLIPR Detection Assays for the Identification of Modulators of the Muscarinic Acetylcholine Receptor 4 (M4).

Authors:  Emery Smith; Peter Chase; Colleen M Niswender; Thomas J Utley; Douglas J Sheffler; Meredith J Noetzel; Atin Lamsal; Michael R Wood; P Jeffrey Conn; Craig W Lindsley; Franck Madoux; Mary Acosta; Louis Scampavia; Timothy Spicer; Peter Hodder
Journal:  J Biomol Screen       Date:  2015-04-15

Review 4.  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

5.  Discovery and SAR of muscarinic receptor subtype 1 (M1) allosteric activators from a molecular libraries high throughput screen. Part 1: 2,5-dibenzyl-2H-pyrazolo[4,3-c]quinolin-3(5H)-ones as positive allosteric modulators.

Authors:  Changho Han; Arindam Chatterjee; Meredith J Noetzel; Joseph D Panarese; Emery Smith; Peter Chase; Peter Hodder; Colleen Niswender; P Jeffrey Conn; Craig W Lindsley; Shaun R Stauffer
Journal:  Bioorg Med Chem Lett       Date:  2014-11-18       Impact factor: 2.823

6.  The Discovery and Characterization of ML218: A Novel, Centrally Active T-Type Calcium Channel Inhibitor with Robust Effects in STN Neurons and in a Rodent Model of Parkinson's Disease.

Authors:  Zixiu Xiang; Analisa D Thompson; John T Brogan; Michael L Schulte; Bruce J Melancon; Debbie Mi; L Michelle Lewis; Bende Zou; Liya Yang; Ryan Morrison; Tammy Santomango; Frank Byers; Katrina Brewer; Jonathan S Aldrich; Haibo Yu; Eric S Dawson; Min Li; Owen McManus; Carrie K Jones; J Scott Daniels; Corey R Hopkins; Ximin Simon Xie; P Jeffrey Conn; C David Weaver; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2011-12-21       Impact factor: 4.418

7.  Isatin replacements applied to the highly selective, muscarinic M1 PAM ML137: continued optimization of an MLPCN probe molecule.

Authors:  Bruce J Melancon; Michael S Poslusney; Patrick R Gentry; James C Tarr; Douglas J Sheffler; Margrith E Mattmann; Thomas M Bridges; Thomas J Utley; J Scott Daniels; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Michael R Wood
Journal:  Bioorg Med Chem Lett       Date:  2012-12-01       Impact factor: 2.823

8.  The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque.

Authors:  Jason M Uslaner; Donnie Eddins; Vanita Puri; Christopher E Cannon; Jane Sutcliffe; Chan Sing Chew; Michelle Pearson; Jeffrey A Vivian; Ronald K Chang; William J Ray; Scott D Kuduk; Marion Wittmann
Journal:  Psychopharmacology (Berl)       Date:  2012-07-24       Impact factor: 4.530

Review 9.  Alzheimer's Disease Therapeutic Approaches.

Authors:  Maria Revi
Journal:  Adv Exp Med Biol       Date:  2020       Impact factor: 2.622

10.  Chemical modification of the M(1) agonist VU0364572 reveals molecular switches in pharmacology and a bitopic binding mode.

Authors:  Gregory J Digby; Thomas J Utley; Atin Lamsal; Christian Sevel; Douglas J Sheffler; Evan P Lebois; Thomas M Bridges; Michael R Wood; Colleen M Niswender; Craig W Lindsley; P Jeffrey Conn
Journal:  ACS Chem Neurosci       Date:  2012-09-09       Impact factor: 4.418
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