Literature DB >> 29683646

PF-06827443 Displays Robust Allosteric Agonist and Positive Allosteric Modulator Activity in High Receptor Reserve and Native Systems.

Sean P Moran1,2,3, Hyekyung P Cho2,3, James Maksymetz2,3, Daniel H Remke2,3, Ryan M Hanson3, Colleen M Niswender2,4,5, Craig W Lindsley2,3,4, Jerri M Rook1,2,3, P Jeffrey Conn1,2,3,5.   

Abstract

Positive allosteric modulators (PAMs) of the M1 subtype of muscarinic acetylcholine receptor have attracted intense interest as an exciting new approach for improving the cognitive deficits in schizophrenia and Alzheimer's disease. Recent evidence suggests that the presence of intrinsic agonist activity of some M1 PAMs may reduce efficacy and contribute to adverse effect liability. However, the M1 PAM PF-06827443 was reported to have only weak agonist activity at human M1 receptors but produced M1-dependent adverse effects. We now report that PF-06827443 is an allosteric agonist in cell lines expressing rat, dog, and human M1 and use of inducible cell lines shows that agonist activity of PF-06827443 is dependent on receptor reserve. Furthermore, PF-06827443 is an agonist in native tissue preparations and induces behavioral convulsions in mice similar to other ago-PAMs. These findings suggest that PF-06827443 is a robust ago-PAM, independent of species, in cell lines and native systems.

Entities:  

Keywords:  Alzheimer’s disease; M1; Positive allosteric modulator; ago-PAM; long-term depression; muscarinic acetylcholine receptor; prefrontal cortex; schizophrenia

Mesh：

Substances：

Year:  2018        PMID： 29683646      PMCID： PMC6146053          DOI： 10.1021/acschemneuro.8b00106

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


  27 in total

1.  Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice.

Authors:  Stephan G Anagnostaras; Geoffrey G Murphy; Susan E Hamilton; Scott L Mitchell; Nancy P Rahnama; Neil M Nathanson; Alcino J Silva
Journal:  Nat Neurosci       Date:  2003-01       Impact factor: 24.884

2.  Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models.

Authors:  Gregory J Digby; Meredith J Noetzel; Michael Bubser; Thomas J Utley; Adam G Walker; Nellie E Byun; Evan P Lebois; Zixiu Xiang; Douglas J Sheffler; Hyekyung P Cho; Albert A Davis; Natali E Nemirovsky; Sarah E Mennenga; Bryan W Camp; Heather A Bimonte-Nelson; Jacob Bode; Kimberly Italiano; Ryan Morrison; J Scott Daniels; Colleen M Niswender; M Foster Olive; Craig W Lindsley; Carrie K Jones; P Jeffrey Conn
Journal:  J Neurosci       Date:  2012-06-20       Impact factor: 6.167

3.  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

4.  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

5.  Challenges in the development of an M4 PAM in vivo tool compound: The discovery of VU0467154 and unexpected DMPK profiles of close analogs.

Authors:  Michael R Wood; Meredith J Noetzel; Michael S Poslusney; Bruce J Melancon; James C Tarr; Atin Lamsal; Sichen Chang; Vincent B Luscombe; Rebecca L Weiner; Hyekyung P Cho; Michael Bubser; Carrie K Jones; Colleen M Niswender; Michael W Wood; Darren W Engers; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2016-11-30       Impact factor: 2.823

6.  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

7.  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

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

Review 10.  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
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  8 in total

1.  A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity.

Authors:  Jerri M Rook; Jeanette L Bertron; Hyekyung P Cho; Pedro M Garcia-Barrantes; Sean P Moran; James T Maksymetz; Kellie D Nance; Jonathan W Dickerson; Daniel H Remke; Sichen Chang; Joel M Harp; Anna L Blobaum; Colleen M Niswender; Carrie K Jones; Shaun R Stauffer; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2018-05-08       Impact factor: 4.418

2.  Clinical and Preclinical Evidence for M1 Muscarinic Acetylcholine Receptor Potentiation as a Therapeutic Approach for Rett Syndrome.

Authors:  Mackenzie Smith; Bright Arthur; Jakub Cikowski; Calista Holt; Sonia Gonzalez; Nicole M Fisher; Sheryl Anne D Vermudez; Craig W Lindsley; Colleen M Niswender; Rocco G Gogliotti
Journal:  Neurotherapeutics       Date:  2022-06-07       Impact factor: 6.088

3.  VU6007477, a Novel M1 PAM Based on a Pyrrolo[2,3-b]pyridine Carboxamide Core Devoid of Cholinergic Adverse Events.

Authors:  Julie L Engers; Elizabeth S Childress; Madeline F Long; Rory A Capstick; Vincent B Luscombe; Hekyung P Cho; Jonathan W Dickerson; Jerri M Rook; Anna L Blobaum; Colleen M Niswender; Darren W Engers; P Jeffrey Conn; Craig W Lindsley
Journal:  ACS Med Chem Lett       Date:  2018-09-04       Impact factor: 4.345

4.  Biased M1 receptor-positive allosteric modulators reveal role of phospholipase D in M1-dependent rodent cortical plasticity.

Authors:  Sean P Moran; Zixiu Xiang; Catherine A Doyle; James Maksymetz; Xiaohui Lv; Sehr Faltin; Nicole M Fisher; Colleen M Niswender; Jerri M Rook; Craig W Lindsley; P Jeffrey Conn
Journal:  Sci Signal       Date:  2019-12-03       Impact factor: 8.192

Review 5.  Targeting Muscarinic Acetylcholine Receptors for the Treatment of Psychiatric and Neurological Disorders.

Authors:  Sean P Moran; James Maksymetz; P Jeffrey Conn
Journal:  Trends Pharmacol Sci       Date:  2019-11-08       Impact factor: 14.819

6.  T-495, a novel low cooperative M1 receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk.

Authors:  Takao Mandai; Yuu Sako; Emi Kurimoto; Yuji Shimizu; Minoru Nakamura; Makoto Fushimi; Ryouta Maeda; Maki Miyamoto; Haruhide Kimura
Journal:  Pharmacol Res Perspect       Date:  2020-02

7.  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

Review 8.  Adenosine Receptor Profiling Reveals an Association between the Presence of Spare Receptors and Cardiovascular Disorders.

Authors:  Emmanuel Fenouillet; Giovanna Mottola; Nathalie Kipson; Franck Paganelli; Régis Guieu; Jean Ruf
Journal:  Int J Mol Sci       Date:  2019-11-27       Impact factor: 5.923
  8 in total

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