Literature DB >> 27173801

Further optimization of the M1 PAM VU0453595: Discovery of novel heterobicyclic core motifs with improved CNS penetration.

Joseph D Panarese1, Hykeyung P Cho1, Jeffrey J Adams1, Kellie D Nance2, Pedro M Garcia-Barrantes1, Sichen Chang1, Ryan D Morrison1, Anna L Blobaum3, Colleen M Niswender4, Shaun R Stauffer5, P Jeffrey Conn4, Craig W Lindsley6.   

Abstract

This Letter describes the continued chemical optimization of the VU0453595 series of M1 positive allosteric modulators (PAMs). By surveying alternative 5,6- and 6,6-heterobicylic cores for the 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one core of VU453595, we found new cores that engendered not only comparable or improved M1 PAM potency, but significantly improved CNS distribution (Kps 0.3-3.1). Moreover, this campaign provided fundamentally distinct M1 PAM chemotypes, greatly expanding the available structural diversity for this valuable CNS target, devoid of hydrogen-bond donors.
Copyright © 2016 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  CNS penetration; M(1); Muscarinic acetylcholine receptor; Positive allosteric modulator (PAM); Structure–activity relationship (SAR)

Mesh：

Substances：

Year:  2016        PMID： 27173801      PMCID： PMC5082649          DOI： 10.1016/j.bmcl.2016.04.083

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


  37 in total

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2.  Unique signaling profiles of positive allosteric modulators of metabotropic glutamate receptor subtype 5 determine differences in in vivo activity.

Authors:  Jerri M Rook; Meredith J Noetzel; Wendy A Pouliot; Thomas M Bridges; Paige N Vinson; Hyekyung P Cho; Ya Zhou; Rocco D Gogliotti; Jason T Manka; Karen J Gregory; Shaun R Stauffer; F Edward Dudek; Zixiu Xiang; Colleen M Niswender; J Scott Daniels; Carrie K Jones; Craig W Lindsley; P Jeffrey Conn
Journal:  Biol Psychiatry       Date:  2012-11-07       Impact factor: 13.382

3.  M1 receptors play a central role in modulating AD-like pathology in transgenic mice.

Authors:  Antonella Caccamo; Salvatore Oddo; Lauren M Billings; Kim N Green; Hilda Martinez-Coria; Abraham Fisher; Frank M LaFerla
Journal:  Neuron       Date:  2006-03-02       Impact factor: 17.173

4.  Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators.

Authors:  Scott D Kuduk; Christina N Di Marco; Jonathan R Saffold; William J Ray; Lei Ma; Marion Wittmann; Kenneth A Koeplinger; Charles D Thompson; George D Hartman; Mark T Bilodeau; Douglas C Beshore
Journal:  Bioorg Med Chem Lett       Date:  2014-01-13       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.  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

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
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  6 in total

1.  Diverse Effects on M1 Signaling and Adverse Effect Liability within a Series of M1 Ago-PAMs.

Authors:  Jerri M Rook; Masahito Abe; Hyekyung P Cho; Kellie D Nance; Vincent B Luscombe; Jeffrey J Adams; Jonathan W Dickerson; Daniel H Remke; Pedro M Garcia-Barrantes; Darren W Engers; Julie L Engers; Sichen Chang; Jarrett J Foster; Anna L Blobaum; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2017-01-10       Impact factor: 4.418

Review 2.  Drug Design Targeting the Muscarinic Receptors and the Implications in Central Nervous System Disorders.

Authors:  Chad R Johnson; Brian D Kangas; Emily M Jutkiewicz; Jack Bergman; Andrew Coop
Journal:  Biomedicines       Date:  2022-02-07

3.  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

4.  M1-positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition.

Authors:  Sean P Moran; Jonathan W Dickerson; Hyekyung P Cho; Zixiu Xiang; James Maksymetz; Daniel H Remke; Xiaohui Lv; Catherine A Doyle; Deepa H Rajan; Colleen M Niswender; Darren W Engers; Craig W Lindsley; Jerri M Rook; P Jeffrey Conn
Journal:  Neuropsychopharmacology       Date:  2018-03-14       Impact factor: 7.853

Review 5.  Fine Tuning Muscarinic Acetylcholine Receptor Signaling Through Allostery and Bias.

Authors:  Emma T van der Westhuizen; K H Christopher Choy; Celine Valant; Simon McKenzie-Nickson; Sophie J Bradley; Andrew B Tobin; Patrick M Sexton; Arthur Christopoulos
Journal:  Front Pharmacol       Date:  2021-01-29       Impact factor: 5.810

6.  Discovery of a novel class of heteroaryl-pyrrolidinones as positive allosteric modulators of the muscarinic acetylcholine receptor M1.

Authors:  Paul K Spearing; Hyekyung P Cho; Vincent B Luscombe; Anna L Blobaum; Olivier Boutaud; Darren W Engers; Alice L Rodriguez; Colleen M Niswender; P Jeffrey Conn; Craig W Lindsley; Aaron M Bender
Journal:  Bioorg Med Chem Lett       Date:  2021-06-09       Impact factor: 2.940
  6 in total

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