Literature DB >> 34710625

Discovery of structurally distinct tricyclic M4 positive allosteric modulator (PAM) chemotypes - Part 2.

Madeline F Long1, Rory A Capstick1, Paul K Spearing1, Julie L Engers1, Alison R Gregro1, Sean R Bollinger1, Sichen Chang1, Vincent B Luscombe1, Alice L Rodriguez1, Hyekyung P Cho1, Colleen M Niswender2, Thomas M Bridges1, P Jeffrey Conn2, Craig W Lindsley3, Darren W Engers1, Kayla J Temple4.   

Abstract

This Letter details our efforts to develop novel tricyclic M4 PAM scaffolds with improved pharmacological properties. This endeavor involved a "tie-back" strategy to replace the 3-amino-4,6-dimethylthieno[2,3-b]pyridine-2-carboxamide core which lead to the discovery of two novel tricyclic cores: a 7,9-dimethylpyrido[3',2':4,5]thieno[3,2-d]pyrimidine core and 2,4-dimethylthieno[2,3-b:5,4-c']dipyridine core. Both tricyclic cores displayed low nanomolar potency against the human M4 receptor.
Copyright © 2021 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  M(4); Muscarinic acetylcholine receptor; Positive Allosteric modulator (PAM); Structure Activity Relationship (SAR)

Mesh：

Substances：

Year:  2021        PMID： 34710625      PMCID： PMC8648000          DOI： 10.1016/j.bmcl.2021.128416

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


  29 in total

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Authors:  Carrie K Jones; Nellie Byun; Michael Bubser
Journal:  Neuropsychopharmacology       Date:  2011-09-28       Impact factor: 7.853

Review 2.  The antipsychotic potential of muscarinic allosteric modulation.

Authors:  Thomas M Bridges; Evan P LeBois; Corey R Hopkins; Michael R Wood; Carrie K Jones; P Jeffrey Conn; Craig W Lindsley
Journal:  Drug News Perspect       Date:  2010-05

3.  Allosteric antipsychotics: m4 muscarinic potentiators as novel treatments for schizophrenia.

Authors:  Martilias Farrell; Bryan L Roth
Journal:  Neuropsychopharmacology       Date:  2010-03       Impact factor: 7.853

Review 4.  CNS drug design: balancing physicochemical properties for optimal brain exposure.

Authors:  Zoran Rankovic
Journal:  J Med Chem       Date:  2015-01-06       Impact factor: 7.446

Review 5.  Muscarinic acetylcholine receptors: novel opportunities for drug development.

Authors:  Andrew C Kruse; Brian K Kobilka; Dinesh Gautam; Patrick M Sexton; Arthur Christopoulos; Jürgen Wess
Journal:  Nat Rev Drug Discov       Date:  2014-06-06       Impact factor: 84.694

6.  Central Nervous System Multiparameter Optimization Desirability: Application in Drug Discovery.

Authors:  Travis T Wager; Xinjun Hou; Patrick R Verhoest; Anabella Villalobos
Journal:  ACS Chem Neurosci       Date:  2016-04-04       Impact factor: 4.418

7.  Discovery of a novel 2,4-dimethylquinoline-6-carboxamide M4 positive allosteric modulator (PAM) chemotype via scaffold hopping.

Authors:  Madeline F Long; Julie L Engers; Sichen Chang; Xiaoyan Zhan; Rebecca L Weiner; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Darren W Engers; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2017-10-09       Impact factor: 2.823

8.  M4 Muscarinic Receptor Signaling Ameliorates Striatal Plasticity Deficits in Models of L-DOPA-Induced Dyskinesia.

Authors:  Weixing Shen; Joshua L Plotkin; Veronica Francardo; Wai Kin D Ko; Zhong Xie; Qin Li; Tim Fieblinger; Jürgen Wess; Richard R Neubig; Craig W Lindsley; P Jeffrey Conn; Paul Greengard; Erwan Bezard; M Angela Cenci; D James Surmeier
Journal:  Neuron       Date:  2015-11-18       Impact factor: 17.173

9.  Discovery of a selective M₄ positive allosteric modulator based on the 3-amino-thieno[2,3-b]pyridine-2-carboxamide scaffold: development of ML253, a potent and brain penetrant compound that is active in a preclinical model of schizophrenia.

Authors:  Uyen Le; Bruce J Melancon; Thomas M Bridges; Paige N Vinson; Thomas J Utley; Atin Lamsal; Alice L Rodriguez; Daryl Venable; Douglas J Sheffler; Carrie K Jones; Anna L Blobaum; Michael R Wood; J Scott Daniels; P Jeffrey Conn; Colleen M Niswender; Craig W Lindsley; Corey R Hopkins
Journal:  Bioorg Med Chem Lett       Date:  2012-11-01       Impact factor: 2.823

10.  Selective activation of M4 muscarinic acetylcholine receptors reverses MK-801-induced behavioral impairments and enhances associative learning in rodents.

Authors:  Michael Bubser; Thomas M Bridges; Ditte Dencker; Robert W Gould; Michael Grannan; Meredith J Noetzel; Atin Lamsal; Colleen M Niswender; J Scott Daniels; Michael S Poslusney; Bruce J Melancon; James C Tarr; Frank W Byers; Jürgen Wess; Mark E Duggan; John Dunlop; Michael W Wood; Nicholas J Brandon; Michael R Wood; Craig W Lindsley; P Jeffrey Conn; Carrie K Jones
Journal:  ACS Chem Neurosci       Date:  2014-08-19       Impact factor: 4.418
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