Literature DB >> 23416001

Spirocyclic replacements for the isatin in the highly selective, muscarinic M1 PAM ML137: the continued optimization of an MLPCN probe molecule.

Michael S Poslusney1, Bruce J Melancon, Patrick R Gentry, Douglas J Sheffler, Thomas M Bridges, Thomas J Utley, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley, Michael R Wood.   

Abstract

This Letter describes the further optimization of an MLPCN probe molecule (ML137) through the introduction of 5- and 6-membered spirocycles in place of the isatin ketone. Interestingly divergent structure-activity relationships, when compared to earlier M1 PAMs, are presented. These novel spirocycles possess improved efficacy relative to ML137, while also maintaining high selectivity for the human and rat muscarinic M1 receptor subtype.
Copyright © 2013 Elsevier Ltd. All rights reserved.

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Year:  2013        PMID： 23416001      PMCID： PMC3594472          DOI： 10.1016/j.bmcl.2013.01.017

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


  15 in total

1.  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

2.  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

3.  Discovery of N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicatinamide, ML293, as a novel, selective and brain penetrant positive allosteric modulator of the muscarinic 4 (M4) receptor.

Authors:  James M Salovich; Paige N Vinson; Douglas J Sheffler; Atin Lamsal; Thomas J Utley; Anna L Blobaum; Thomas M Bridges; Uyen Le; Carrie K Jones; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley; Corey R Hopkins
Journal:  Bioorg Med Chem Lett       Date:  2012-06-06       Impact factor: 2.823

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

Review 5.  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

6.  Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM.

Authors:  Thomas M Bridges; J Phillip Kennedy; Hyekyung P Cho; Micah L Breininger; Patrick R Gentry; Corey R Hopkins; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2009-11-22       Impact factor: 2.823

7.  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

8.  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

9.  Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia.

Authors:  Anantha Shekhar; William Z Potter; Jeffrey Lightfoot; John Lienemann; Sanjay Dubé; Craig Mallinckrodt; Frank P Bymaster; David L McKinzie; Christian C Felder
Journal:  Am J Psychiatry       Date:  2008-07-01       Impact factor: 18.112

10.  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
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  7 in total

1.  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

Review 2.  Development of M1 mAChR allosteric and bitopic ligands: prospective therapeutics for the treatment of cognitive deficits.

Authors:  Briana J Davie; Arthur Christopoulos; Peter J Scammells
Journal:  ACS Chem Neurosci       Date:  2013-05-23       Impact factor: 4.418

Review 3.  Allosteric modulation of the M1 muscarinic acetylcholine receptor: improving cognition and a potential treatment for schizophrenia and Alzheimer's disease.

Authors:  Bruce J Melancon; James C Tarr; Joseph D Panarese; Michael R Wood; Craig W Lindsley
Journal:  Drug Discov Today       Date:  2013-09-17       Impact factor: 7.851

4.  Structure-Activity Relationships of Pan-Gαq/11 Coupled Muscarinic Acetylcholine Receptor Positive Allosteric Modulators.

Authors:  Alice E Berizzi; Aaron M Bender; Craig W Lindsley; P Jeffrey Conn; Patrick M Sexton; Christopher J Langmead; Arthur Christopoulos
Journal:  ACS Chem Neurosci       Date:  2018-04-30       Impact factor: 4.418

Review 5.  Development of allosteric modulators of GPCRs for treatment of CNS disorders.

Authors:  Hilary Highfield Nickols; P Jeffrey Conn
Journal:  Neurobiol Dis       Date:  2013-09-27       Impact factor: 5.996

6.  Prefrontal Cortex-Mediated Impairments in a Genetic Model of NMDA Receptor Hypofunction Are Reversed by the Novel M1 PAM VU6004256.

Authors:  Michael D Grannan; Catharine A Mielnik; Sean P Moran; Robert W Gould; Jacob Ball; Zhuoyan Lu; Michael Bubser; Amy J Ramsey; Masahito Abe; Hyekyung P Cho; Kellie D Nance; Anna L Blobaum; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Carrie K Jones
Journal:  ACS Chem Neurosci       Date:  2016-10-05       Impact factor: 4.418

7.  The Hypnotic, Anxiolytic, and Antinociceptive Profile of a Novel µ-Opioid Agonist.

Authors:  Guilherme Carneiro Montes; Bianca Nascimento Monteiro da Silva; Bismarck Rezende; Roberto Takashi Sudo; Vitor Francisco Ferreira; Fernando de Carvalho da Silva; Angelo da Cunha Pinto; Bárbara Vasconcellos da Silva; Gisele Zapata-Sudo
Journal:  Molecules       Date:  2017-05-16       Impact factor: 4.411
  7 in total

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