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Bitopic Binding Mode of an M 1 Muscarinic Acetylcholine Receptor Agonist Associated with Adverse Clinical Trial Outcomes.

التفاصيل البيبلوغرافية
العنوان: Bitopic Binding Mode of an M 1 Muscarinic Acetylcholine Receptor Agonist Associated with Adverse Clinical Trial Outcomes.
المؤلفون: Bradley SJ; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Molloy C; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Bundgaard C; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Mogg AJ; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Thompson KJ; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Dwomoh L; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Sanger HE; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Crabtree MD; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Brooke SM; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Sexton PM; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Felder CC; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Christopoulos A; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Broad LM; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.)., Tobin AB; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.) andrew.tobin@glasgow.ac.uk chris.langmead@monash.edu., Langmead CJ; The Centre for Translational Pharmacology, Institute of Molecular, Cell, and Systems Biology, College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, Scotland (S.J.B., C.M., K.J.T., L.D., S.M.B., A.B.T.); Eli Lilly & Co. Neuroscience, Windlesham, Surrey, United Kingdom (C.B., A.J.M., H.E.S., M.D.C., L.M.B.); Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia (P.M.S., A.C., C.J.L.); and Eli Lilly & Co. Neuroscience, Indianapolis, Indiana (C.C.F.) andrew.tobin@glasgow.ac.uk chris.langmead@monash.edu.
المصدر: Molecular pharmacology [Mol Pharmacol] 2018 Jun; Vol. 93 (6), pp. 645-656. Date of Electronic Publication: 2018 Apr 25.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0035623 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0111 (Electronic) Linking ISSN: 0026895X NLM ISO Abbreviation: Mol Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics
مواضيع طبية MeSH: Acetylcholine/*metabolism , Muscarinic Agonists/*pharmacology , Receptor, Muscarinic M1/*metabolism , Receptors, Muscarinic/*metabolism, Allosteric Regulation/drug effects ; Allosteric Site/drug effects ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Animals ; Benzimidazoles/pharmacology ; Binding Sites/drug effects ; CHO Cells ; Cell Line ; Clinical Trials as Topic ; Cricetinae ; Cricetulus ; Humans ; Learning/drug effects ; Male ; Memory/drug effects ; Mice ; Mice, Inbred C57BL ; Protein Binding/drug effects ; Rats ; Rats, Wistar
مستخلص: The realization of the therapeutic potential of targeting the M 1 muscarinic acetylcholine receptor (mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M 1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1 H -benzimidazol-2-one), described previously as a potent M 1 receptor allosteric agonist, which showed procognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M 1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702, together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. Although they impart beneficial effects on learning and memory, we conclude that these properties are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data support the notion that "pure" positive allosteric modulators showing selectivity for the M 1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses.
(Copyright © 2018 by The Author(s).)
References: J Neurosci. 1995 May;15(5 Pt 2):4077-92. (PMID: 7751967)
Mol Pharmacol. 2014 Mar;85(3):492-509. (PMID: 24366668)
Pharmacol Ther. 2008 Feb;117(2):232-43. (PMID: 18082893)
Neurobiol Learn Mem. 1995 Mar;63(2):174-80. (PMID: 7663891)
Nat Neurosci. 2003 Jan;6(1):51-8. (PMID: 12483218)
J Biol Chem. 2014 Feb 28;289(9):6067-79. (PMID: 24443568)
Proc Natl Acad Sci U S A. 2009 Sep 15;106(37):15950-5. (PMID: 19717450)
Annu Rev Pharmacol Toxicol. 2012;52:153-78. (PMID: 21910627)
Psychopharmacology (Berl). 2015 Jun;232(11):1859-66. (PMID: 25491927)
Mol Pharmacol. 2002 Jun;61(6):1297-302. (PMID: 12021390)
Neuropharmacology. 2011 Jan;60(1):24-35. (PMID: 20637785)
ACS Chem Neurosci. 2012 Mar 21;3(3):193-203. (PMID: 22860188)
Trends Pharmacol Sci. 2006 Sep;27(9):475-81. (PMID: 16889837)
Annu Rev Pharmacol Toxicol. 2007;47:1-51. (PMID: 17009927)
Nat Rev Drug Discov. 2009 Jan;8(1):41-54. (PMID: 19116626)
Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5163-8. (PMID: 17360345)
Neuron. 2016 Feb 17;89(4):683-94. (PMID: 26889809)
Arch Neurol. 1997 Apr;54(4):465-73. (PMID: 9109749)
J Pharmacol Exp Ther. 2016 Feb;356(2):293-304. (PMID: 26582730)
Neuropharmacology. 2017 Mar 15;115:100-114. (PMID: 26748052)
J Neurosci. 1988 Dec;8(12):4646-52. (PMID: 3199198)
J Pharmacol Exp Ther. 2015 Dec;355(3):442-50. (PMID: 26446308)
Behav Brain Res. 2015;287:96-9. (PMID: 25800972)
Eur J Pharmacol. 1989 Sep 1;168(1):71-80. (PMID: 2583233)
J Biol Chem. 2016 Apr 22;291(17 ):8862-75. (PMID: 26826123)
Int J Neuropsychopharmacol. 2013 May;16(4):721-31. (PMID: 22932339)
J Biol Chem. 2014 Aug 22;289(34):23817-37. (PMID: 25006252)
Mol Pharmacol. 2013 Feb;83(2):521-30. (PMID: 23197649)
J Neurosci. 2008 Oct 8;28(41):10422-33. (PMID: 18842902)
Mol Pharmacol. 2013 Sep;84(3):425-37. (PMID: 23798605)
J Biol Chem. 2012 Jan 2;287(1):650-9. (PMID: 22086918)
J Med Chem. 2017 Aug 10;60(15):6649-6663. (PMID: 28598634)
ACS Med Chem Lett. 2010 Jun 08;1(6):244-8. (PMID: 24900202)
Mol Pharmacol. 2009 Feb;75(2):331-41. (PMID: 19001633)
J Pharmacol Exp Ther. 1999 May;289(2):946-55. (PMID: 10215674)
Mol Pharmacol. 2011 Feb;79(2):298-307. (PMID: 20978120)
J Clin Invest. 2017 Feb 1;127(2):487-499. (PMID: 27991860)
Neuropsychopharmacology. 2010 Mar;35(4):855-69. (PMID: 19940843)
J Med Chem. 2016 Jul 14;59(13):6313-28. (PMID: 27275946)
معلومات مُعتمدة: United Kingdom Wellcome Trust; 201529/Z/16/Z United Kingdom Wellcome Trust; MR/P019366/1 United Kingdom Medical Research Council; C596/A17196 United Kingdom Cancer Research UK
المشرفين على المادة: 0 (Benzimidazoles)
0 (GSK 1034702)
0 (Muscarinic Agonists)
0 (Receptor, Muscarinic M1)
0 (Receptors, Muscarinic)
43135-91-7 (benzimidazol-2-one)
N9YNS0M02X (Acetylcholine)
تواريخ الأحداث: Date Created: 20180427 Date Completed: 20190201 Latest Revision: 20190201
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5963591
DOI: 10.1124/mol.118.111872
PMID: 29695609
قاعدة البيانات: MEDLINE
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