Warning: Undefined array key "mm" in /www/wwwroot/www.ai-bt.com/si.php on line 10 Deprecated: trim(): Passing null to parameter #1 ($string) of type string is deprecated in /www/wwwroot/www.ai-bt.com/si.php on line 10 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.

Literature DB >> 23177787

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.

Uyen Le¹, 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.

Abstract

Herein we report a next generation muscarinic receptor 4 (M(4)) positive allosteric modulator (PAM), ML253 which exhibits nanomolar activity at both the human (EC(50)=56 nM) and rat (EC(50)=176 nM) receptors and excellent efficacy by the left-ward shift of the ACh concentration response curve (fold shift, human=106; rat=50). In addition, ML253 is selective against the four other muscarinic subtypes, displays excellent CNS exposure and is active in an amphetamine-induced hyperlocomotion assay.

Entities: CellLine Chemical Disease Gene Species

Mesh：

Substances：

Year: 2012 PMID： 23177787 PMCID： PMC3535830 DOI： 10.1016/j.bmcl.2012.10.073

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

15 in total

Review 1. Towards a muscarinic hypothesis of schizophrenia.

Authors: T J Raedler; F P Bymaster; R Tandon; D Copolov; B Dean
Journal: Mol Psychiatry Date: 2006-12-05 Impact factor: 15.992

2. An allosteric potentiator of M4 mAChR modulates hippocampal synaptic transmission.

Authors: Jana K Shirey; Zixiu Xiang; Darren Orton; Ashley E Brady; Kari A Johnson; Richard Williams; Jennifer E Ayala; Alice L Rodriguez; Jürgen Wess; David Weaver; Colleen M Niswender; P Jeffrey Conn
Journal: Nat Chem Biol Date: 2007-12-02 Impact factor: 15.040

Review 3. Molecular biology of muscarinic acetylcholine receptors.

Authors: J Wess
Journal: Crit Rev Neurobiol Date: 1996

4. 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

5. 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

Review 6. Schizophrenia: the fundamental questions.

Authors: N C Andreasen
Journal: Brain Res Brain Res Rev Date: 2000-03

Review 7. 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

8. Allosteric modulation of the muscarinic M4 receptor as an approach to treating schizophrenia.

Authors: W Y Chan; D L McKinzie; S Bose; S N Mitchell; J M Witkin; R C Thompson; A Christopoulos; S Lazareno; N J M Birdsall; F P Bymaster; C C Felder
Journal: Proc Natl Acad Sci U S A Date: 2008-08-04 Impact factor: 11.205

9. Synthesis and structure-activity relationships of allosteric potentiators of the m(4) muscarinic acetylcholine receptor.

Authors: J Phillip Kennedy; Thomas M Bridges; Patrick R Gentry; John T Brogan; Alexander S Kane; Carrie K Jones; Ashley E Brady; Jana K Shirey; P Jeffrey Conn; Craig W Lindsley
Journal: ChemMedChem Date: 2009-10 Impact factor: 3.466

Review 10. Muscarinic acetylcholine receptor knockout mice: novel phenotypes and clinical implications.

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

12 in total

1. Discovery of VU0467485/AZ13713945: An M₄ PAM Evaluated as a Preclinical Candidate for the Treatment of Schizophrenia.

Authors: Michael R Wood; Meredith J Noetzel; Bruce J Melancon; Michael S Poslusney; Kellie D Nance; Miguel A Hurtado; Vincent B Luscombe; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Sichen Chang; Michael Bubser; Anna L Blobaum; Darren W Engers; Colleen M Niswender; Carrie K Jones; Nicholas J Brandon; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal: ACS Med Chem Lett Date: 2016-12-16 Impact factor: 4.345

Review 2. 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

3. Optimization of M₄ positive allosteric modulators (PAMs): The discovery of VU0476406, a non-human primate in vivo tool compound for translational pharmacology.

Authors: Bruce J Melancon; Michael R Wood; Meredith J Noetzel; Kellie D Nance; Eileen M Engelberg; Changho Han; Atin Lamsal; Sichen Chang; Hyekyung P Cho; Frank W Byers; Michael Bubser; Carrie K Jones; Colleen M Niswender; Michael W Wood; Darren W Engers; Dedong Wu; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal: Bioorg Med Chem Lett Date: 2017-04-13 Impact factor: 2.823

4. Discovery and SAR of a novel series of potent, CNS penetrant M4 PAMs based on a non-enolizable ketone core: Challenges in disposition.

Authors: Michael R Wood; Meredith J Noetzel; James C Tarr; Alice L Rodriguez; Atin Lamsal; Sichen Chang; Jarrett J Foster; Emery Smith; Peter Chase; Peter S Hodder; Darren W Engers; Colleen M Niswender; Nicholas J Brandon; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal: Bioorg Med Chem Lett Date: 2016-07-21 Impact factor: 2.823

5. Challenges in the development of an M₄ PAM preclinical candidate: The discovery, SAR, and in vivo characterization of a series of 3-aminoazetidine-derived amides.

Authors: James C Tarr; Michael R Wood; Meredith J Noetzel; Jeanette L Bertron; Rebecca L Weiner; Alice L Rodriguez; Atin Lamsal; Frank W Byers; Sichen Chang; Hyekyung P Cho; Carrie K Jones; Colleen M Niswender; Michael W Wood; Nicholas J Brandon; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal: Bioorg Med Chem Lett Date: 2017-05-06 Impact factor: 2.823

Review 6. 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

7. 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

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

Authors: Madeline F Long; Rory A Capstick; Paul K Spearing; Julie L Engers; Alison R Gregro; Sean R Bollinger; Sichen Chang; Vincent B Luscombe; Alice L Rodriguez; Hyekyung P Cho; Colleen M Niswender; Thomas M Bridges; P Jeffrey Conn; Craig W Lindsley; Darren W Engers; Kayla J Temple
Journal: Bioorg Med Chem Lett Date: 2021-10-26 Impact factor: 2.823

9. Discovery and optimization of a novel series of highly CNS penetrant M4 PAMs based on a 5,6-dimethyl-4-(piperidin-1-yl)thieno[2,3-d]pyrimidine core.

Authors: Michael R Wood; Meredith J Noetzel; Julie L Engers; Katrina A Bollinger; Bruce J Melancon; James C Tarr; Changho Han; Mary West; Alison R Gregro; Atin Lamsal; Sichen Chang; Sonia Ajmera; Emery Smith; Peter Chase; Peter S Hodder; Michael Bubser; Carrie K Jones; Corey R Hopkins; Kyle A Emmitte; Colleen M Niswender; Michael W Wood; Mark E Duggan; P Jeffrey Conn; Thomas M Bridges; Craig W Lindsley
Journal: Bioorg Med Chem Lett Date: 2016-05-05 Impact factor: 2.823

Review 10. 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