Literature DB >> 22507963

Continued optimization of the MLPCN probe ML071 into highly potent agonists of the hM1 muscarinic acetylcholine receptor.

Bruce J Melancon1, Rocco D Gogliotti, James C Tarr, Sam A Saleh, Brian A Chauder, Evan P Lebois, Hyekyung P Cho, Thomas J Utley, Douglas J Sheffler, Thomas M Bridges, Ryan D Morrison, J Scott Daniels, Colleen M Niswender, P Jeffrey Conn, Craig W Lindsley, Michael R Wood.   

Abstract

This Letter describes the continued optimization of the MLPCN probe molecule ML071. After introducing numerous cyclic constraints and novel substitutions throughout the parent structure, we produced a number of more highly potent agonists of the M(1) mACh receptor. While many novel agonists demonstrated a promising ability to increase soluble APPα release, further characterization indicated they may be functioning as bitopic agonists. These results and the implications of a bitopic mode of action are presented.
Copyright © 2012 Elsevier Ltd. All rights reserved.

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Year:  2012        PMID： 22507963      PMCID： PMC3348459          DOI： 10.1016/j.bmcl.2012.03.088

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


  14 in total

1.  Development of a highly selective, orally bioavailable and CNS penetrant M1 agonist derived from the MLPCN probe ML071.

Authors:  Evan P Lebois; Gregory J Digby; Douglas J Sheffler; Bruce J Melancon; James C Tarr; Hyekyung P Cho; Nicole R Miller; Ryan Morrison; Thomas M Bridges; Zixiu Xiang; J Scott Daniels; Michael R Wood; P Jeffrey Conn; Craig W Lindsley
Journal:  Bioorg Med Chem Lett       Date:  2011-08-24       Impact factor: 2.823

2.  Discovery and characterization of novel subtype-selective allosteric agonists for the investigation of M(1) receptor function in the central nervous system.

Authors:  Evan P Lebois; Thomas M Bridges; L Michelle Lewis; Eric S Dawson; Alexander S Kane; Zixiu Xiang; Satyawan B Jadhav; Huiyong Yin; J Phillip Kennedy; Jens Meiler; Colleen M Niswender; Carrie K Jones; P Jeffrey Conn; C David Weaver; Craig W Lindsley
Journal:  ACS Chem Neurosci       Date:  2010       Impact factor: 4.418

Review 3.  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

4.  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

5.  Quinolizidinone carboxylic acids as CNS penetrant, selective m1 allosteric muscarinic receptor modulators.

Authors:  Scott D Kuduk; Ronald K Chang; Christina N Di Marco; William J Ray; Lei Ma; Marion Wittmann; Matthew A Seager; Kenneth A Koeplinger; Charles D Thompson; George D Hartman; Mark T Bilodeau
Journal:  ACS Med Chem Lett       Date:  2010-06-04       Impact factor: 4.345

6.  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 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.  AC-260584, an orally bioavailable M(1) muscarinic receptor allosteric agonist, improves cognitive performance in an animal model.

Authors:  Stefania Risso Bradley; Jelveh Lameh; Linda Ohrmund; Thomas Son; Abhishek Bajpai; Derek Nguyen; Mikael Friberg; Ethan S Burstein; Tracy A Spalding; Thomas R Ott; Hans H Schiffer; Ali Tabatabaei; Krista McFarland; Robert E Davis; Douglas W Bonhaus
Journal:  Neuropharmacology       Date:  2009-10-14       Impact factor: 5.250

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.  Discovery of the first highly M5-preferring muscarinic acetylcholine receptor ligand, an M5 positive allosteric modulator derived from a series of 5-trifluoromethoxy N-benzyl isatins.

Authors:  Thomas M Bridges; Joy E Marlo; Colleen M Niswender; Carrie K Jones; Satyawan B Jadhav; Patrick R Gentry; Hyekyung C Plumley; C David Weaver; P Jeffrey Conn; Craig W Lindsley
Journal:  J Med Chem       Date:  2009-06-11       Impact factor: 7.446
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  8 in total

Review 1.  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

2.  Discovery of novel N-substituted oxindoles as selective m1 and m4 muscarinic acetylcholine receptors partial agonists.

Authors:  Takaaki Sumiyoshi; Takeshi Enomoto; Kentaro Takai; Yoko Takahashi; Yasuko Konishi; Yoshiharu Uruno; Kengo Tojo; Atsushi Suwa; Harumi Matsuda; Tomokazu Nakako; Mutsuko Sakai; Atsushi Kitamura; Yasuaki Uematsu; Akihiko Kiyoshi
Journal:  ACS Med Chem Lett       Date:  2013-01-27       Impact factor: 4.345

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.  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

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

Authors:  Michael S Poslusney; 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
Journal:  Bioorg Med Chem Lett       Date:  2013-01-11       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

Review 7.  New pharmacological approaches to the cholinergic system: an overview on muscarinic receptor ligands and cholinesterase inhibitors.

Authors:  Nigel H Greig; Marcella Reale; Ada M Tata
Journal:  Recent Pat CNS Drug Discov       Date:  2013-08

Review 8.  Multitargeting nature of muscarinic orthosteric agonists and antagonists.

Authors:  Jaromir Myslivecek
Journal:  Front Physiol       Date:  2022-09-06       Impact factor: 4.755
  8 in total

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