Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs

Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on...

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Published inNature chemical biology Vol. 16; no. 3; pp. 240 - 249
Main Authors Bradley, Sophie J., Molloy, Colin, Valuskova, Paulina, Dwomoh, Louis, Scarpa, Miriam, Rossi, Mario, Finlayson, Lisa, Svensson, Kjell A., Chernet, Eyassu, Barth, Vanessa N., Gherbi, Karolina, Sykes, David A., Wilson, Caroline A., Mistry, Rajendra, Sexton, Patrick M., Christopoulos, Arthur, Mogg, Adrian J., Rosethorne, Elizabeth M., Sakata, Shuzo, John Challiss, R. A., Broad, Lisa M., Tobin, Andrew B.
Format Journal Article
LanguageEnglish
Published New York Nature Publishing Group US 01.03.2020
Nature Publishing Group
Subjects
631/154
631/154/436
631/378/340
631/92/96
Acetylcholine receptors (muscarinic)
Acetylcholinesterase - metabolism
Alzheimer Disease - drug therapy
Alzheimer's disease
Animal models
Animals
Anxiety
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Cholinergic Agents - pharmacology
Cholinergics
Cholinesterase
Cholinesterase inhibitors
Cholinesterase Inhibitors - metabolism
Cholinesterase Inhibitors - pharmacology
Disease Models, Animal
Drug Design
Drug development
Epilepsy
Female
G protein-coupled receptors
Gene Knock-In Techniques
Ligands
Locomotion
Male
Mapping
Medical treatment
Mice
Mice, Inbred C57BL
Mutants
Neurodegenerative diseases
Phosphorylation
Proteins
Receptor, Muscarinic M1 - genetics
Receptor, Muscarinic M1 - metabolism
Receptors
Seizures
Side effects
Signaling
Therapeutic applications
Online AccessGet full text

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Abstract Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including ‘epileptic-like’ seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD. Use of receptor variants in knock-in mice to dissect phosphorylation-dependent signaling from G protein-dependent signaling mediated by acetylcholine receptor M1 mAChR defines the ability of receptor ligands to modulate anxiety and locomotion behaviors.
AbstractList Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including ‘epileptic-like’ seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.Use of receptor variants in knock-in mice to dissect phosphorylation-dependent signaling from G protein-dependent signaling mediated by acetylcholine receptor M1 mAChR defines the ability of receptor ligands to modulate anxiety and locomotion behaviors.
Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including ‘epileptic-like’ seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.
Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including ‘epileptic-like’ seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD. Use of receptor variants in knock-in mice to dissect phosphorylation-dependent signaling from G protein-dependent signaling mediated by acetylcholine receptor M1 mAChR defines the ability of receptor ligands to modulate anxiety and locomotion behaviors.
Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including 'epileptic-like' seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1 muscarinic acetylcholine receptors (M1 mAChRs) represent a potential alternate therapeutic target; however, drug discovery programs focused on this G protein-coupled receptor (GPCR) have failed, largely due to cholinergic adverse responses. Employing novel chemogenetic and phosphorylation-deficient, G protein-biased, mouse models, paired with a toolbox of probe molecules, we establish previously unappreciated pharmacologically targetable M1 mAChR neurological processes, including anxiety-like behaviors and hyper-locomotion. By mapping the upstream signaling pathways regulating these responses, we determine the importance of receptor phosphorylation-dependent signaling in driving clinically relevant outcomes and in controlling adverse effects including 'epileptic-like' seizures. We conclude that M1 mAChR ligands that promote receptor phosphorylation-dependent signaling would protect against cholinergic adverse effects in addition to driving beneficial responses such as learning and memory and anxiolytic behavior relevant for the treatment of AD.
Author Christopoulos, Arthur
Chernet, Eyassu
Finlayson, Lisa
Rosethorne, Elizabeth M.
Mistry, Rajendra
Sakata, Shuzo
Svensson, Kjell A.
Tobin, Andrew B.
Valuskova, Paulina
Scarpa, Miriam
Mogg, Adrian J.
Barth, Vanessa N.
John Challiss, R. A.
Sexton, Patrick M.
Gherbi, Karolina
Broad, Lisa M.
Molloy, Colin
Dwomoh, Louis
Sykes, David A.
Wilson, Caroline A.
Rossi, Mario
Bradley, Sophie J.
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BackLink https://www.ncbi.nlm.nih.gov/pubmed/32080630$$D View this record in MEDLINE/PubMed
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Cites_doi 10.1074/jbc.M115.681726
10.1124/jpet.115.226910
10.1126/scisignal.2001707
10.1016/j.pharmthera.2005.09.008
10.1016/j.tips.2004.06.006
10.1038/s41467-019-09204-y
10.1021/acsptsci.8b00012
10.1074/jbc.M110.154526
10.1021/ml100105x
10.1080/07420520600827111
10.1021/acs.jmedchem.7b00597
10.1124/mol.113.088880
10.1002/anie.201301924
10.1038/nrd2760
10.1016/j.neuron.2016.01.040
10.1073/pnas.261583798
10.1124/jpet.117.243774
10.1038/nrd.2017.229
10.1124/jpet.117.246454
10.1073/pnas.0700293104
10.1021/acschemneuro.7b00001
10.1126/science.7046051
10.1017/S1461145712000752
10.1016/j.neuropharm.2018.01.028
10.1016/j.jneumeth.2015.03.009
10.1016/S0140-6736(04)16499-4
10.1038/s41386-018-0033-9
10.1021/acschemneuro.8b00131
10.1523/JNEUROSCI.21-14-05239.2001
10.1021/acs.jmedchem.6b00544
10.1016/0166-4328(83)90136-5
10.1111/j.1528-1157.1996.tb00541.x
10.1172/JCI87526
10.3389/fnagi.2019.00029
10.1124/mol.66.2.260
10.1073/pnas.0914801107
10.1124/mol.108.052886
10.1021/acschemneuro.6b00429
10.1038/npp.2015.189
10.1073/pnas.1722336115
10.1073/pnas.1011651107
10.1001/archneur.1997.00550160091022
10.1523/JNEUROSCI.3930-09.2009
10.1124/mol.118.111872
10.1097/00002093-199703000-00004
10.1073/pnas.1521706113
10.1016/S0006-291X(88)80304-8
10.1016/j.tem.2006.03.008
10.1016/j.cell.2017.07.002
10.1523/JNEUROSCI.0337-12.2012
10.1038/nature12120
10.1016/j.nbd.2013.09.013
10.1124/mol.115.101949
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References van der Westhuizen, Breton, Christopoulos, Bouvier (CR54) 2014; 85
Armbruster, Li, Pausch, Herlitze, Roth (CR19) 2007; 104
Gurevich, Gurevich (CR37) 2006; 110
Digby (CR5) 2012; 32
Smith, Lefkowitz, Rajagopal (CR17) 2018; 17
Lefkowitz (CR46) 2013; 52
Ghoshal (CR6) 2016; 41
Gerber (CR22) 2001; 98
Zhou (CR39) 2017; 170
Arraj, Lemmer (CR52) 2006; 23
Levesque, Avoli, Bernard (CR32) 2016; 260
Butcher (CR25) 2016; 291
Turski (CR33) 1983; 9
Nickols, Conn (CR16) 2014; 61
Cavalheiro, Santos, Priel (CR31) 1996; 37
Butcher (CR42) 2011; 286
Reiter, Lefkowitz (CR24) 2006; 17
Bodick (CR9) 1997; 54
Felder (CR30) 2018; 136
Mayer (CR40) 2019; 10
Shirey (CR8) 2009; 29
Kong (CR44) 2010; 107
Alt (CR27) 2016; 356
Bartus, Dean, Beer, Lippa (CR1) 1982; 217
Courtney (CR2) 2004; 363
Nobles (CR43) 2011; 4
Mogg (CR34) 2018; 365
Thompson (CR21) 2018; 1
Challiss, Batty, Nahorski (CR51) 1988; 157
Inglis (CR3) 2002; 127
Rook (CR50) 2018; 9
Bradley (CR23) 2016; 113
Prihandoko (CR36) 2016; 89
Rook (CR15) 2017; 8
Davoren (CR29) 2016; 59
Nathan (CR12) 2013; 16
Bender, Jones, Lindsley (CR35) 2017; 8
Roth (CR20) 2016; 89
Bradley (CR4) 2017; 127
Moran (CR7) 2018; 43
Shukla (CR38) 2013; 497
Poulin (CR45) 2010; 107
Budzik (CR11) 2010; 1
Miyakawa, Yamada, Duttaroy, Wess (CR48) 2001; 21
Lyngholm, Sakata (CR53) 2019; 11
Marlo (CR18) 2009; 75
Bradley (CR10) 2018; 93
Lefkowitz (CR47) 2004; 25
Staus (CR41) 2018; 115
Conn, Christopoulos, Lindsley (CR13) 2009; 8
Davoren (CR14) 2017; 60
Kurimoto (CR49) 2018; 364
Gautam (CR26) 2004; 66
Bodick (CR28) 1997; 11
AJ Butcher (453_CR25) 2016; 291
NC Bodick (453_CR28) 1997; 11
D Lyngholm (453_CR53) 2019; 11
CC Felder (453_CR30) 2018; 136
VV Gurevich (453_CR37) 2006; 110
E Reiter (453_CR24) 2006; 17
T Miyakawa (453_CR48) 2001; 21
SJ Bradley (453_CR23) 2016; 113
F Inglis (453_CR3) 2002; 127
DJ Gerber (453_CR22) 2001; 98
KJ Thompson (453_CR21) 2018; 1
JM Rook (453_CR50) 2018; 9
BN Armbruster (453_CR19) 2007; 104
AM Bender (453_CR35) 2017; 8
KC Kong (453_CR44) 2010; 107
KN Nobles (453_CR43) 2011; 4
GJ Digby (453_CR5) 2012; 32
R Prihandoko (453_CR36) 2016; 89
SP Moran (453_CR7) 2018; 43
HH Nickols (453_CR16) 2014; 61
E Kurimoto (453_CR49) 2018; 364
RJ Lefkowitz (453_CR47) 2004; 25
ET van der Westhuizen (453_CR54) 2014; 85
DP Staus (453_CR41) 2018; 115
M Arraj (453_CR52) 2006; 23
RT Bartus (453_CR1) 1982; 217
JM Rook (453_CR15) 2017; 8
RJ Lefkowitz (453_CR46) 2013; 52
WA Turski (453_CR33) 1983; 9
NC Bodick (453_CR9) 1997; 54
JE Davoren (453_CR14) 2017; 60
JS Smith (453_CR17) 2018; 17
SJ Bradley (453_CR4) 2017; 127
AJ Butcher (453_CR42) 2011; 286
A Alt (453_CR27) 2016; 356
M Levesque (453_CR32) 2016; 260
A Ghoshal (453_CR6) 2016; 41
B Budzik (453_CR11) 2010; 1
C Courtney (453_CR2) 2004; 363
RA Challiss (453_CR51) 1988; 157
D Gautam (453_CR26) 2004; 66
JE Marlo (453_CR18) 2009; 75
D Mayer (453_CR40) 2019; 10
JE Davoren (453_CR29) 2016; 59
B Poulin (453_CR45) 2010; 107
PJ Conn (453_CR13) 2009; 8
JK Shirey (453_CR8) 2009; 29
SJ Bradley (453_CR10) 2018; 93
EA Cavalheiro (453_CR31) 1996; 37
XE Zhou (453_CR39) 2017; 170
AK Shukla (453_CR38) 2013; 497
PJ Nathan (453_CR12) 2013; 16
BL Roth (453_CR20) 2016; 89
AJ Mogg (453_CR34) 2018; 365
32080631 - Nat Chem Biol. 2020 Mar;16(3):226-227. doi: 10.1038/s41589-020-0468-2.
References_xml – volume: 75
  start-page: 577
  year: 2009
  end-page: 588
  ident: CR18
  article-title: Discovery and characterization of novel allosteric potentiators of M muscarinic receptors reveals multiple modes of activity
  publication-title: Mol. Pharmacol.
– volume: 170
  start-page: 457
  year: 2017
  end-page: 469
  ident: CR39
  article-title: Identification of phosphorylation codes for arrestin recruitment by G protein-coupled receptors
  publication-title: Cell
– volume: 110
  start-page: 465
  year: 2006
  end-page: 502
  ident: CR37
  article-title: The structural basis of arrestin-mediated regulation of G-protein-coupled receptors
  publication-title: Pharmacol. Ther.
– volume: 16
  start-page: 721
  year: 2013
  end-page: 731
  ident: CR12
  article-title: The potent M1 receptor allosteric agonist GSK1034702 improves episodic memory in humans in the nicotine abstinence model of cognitive dysfunction
  publication-title: Int. J. Neuropsychopharmacol.
– volume: 17
  start-page: 243
  year: 2018
  end-page: 260
  ident: CR17
  article-title: Biased signalling: from simple switches to allosteric microprocessors
  publication-title: Nat. Rev. Drug Discov.
– volume: 11
  start-page: S16
  year: 1997
  end-page: S22
  ident: CR28
  article-title: The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease
  publication-title: Alzheimer Dis. Assoc. Disord.
– volume: 260
  start-page: 45
  year: 2016
  end-page: 52
  ident: CR32
  article-title: Animal models of temporal lobe epilepsy following systemic chemoconvulsant administration
  publication-title: J. Neurosci. Methods
– volume: 127
  start-page: 487
  year: 2017
  end-page: 499
  ident: CR4
  article-title: M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss
  publication-title: J. Clin. Invest.
– volume: 104
  start-page: 5163
  year: 2007
  end-page: 5168
  ident: CR19
  article-title: Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand
  publication-title: Proc. Natl Acad. Sci. USA
– volume: 52
  start-page: 6366
  year: 2013
  end-page: 6378
  ident: CR46
  article-title: A brief history of G-protein coupled receptors (Nobel Lecture)
  publication-title: Angew. Chem.
– volume: 37
  start-page: 1015
  year: 1996
  end-page: 1019
  ident: CR31
  article-title: The pilocarpine model of epilepsy in mice
  publication-title: Epilepsia
– volume: 9
  start-page: 2274
  year: 2018
  end-page: 2285
  ident: CR50
  article-title: A novel M PAM VU0486846 exerts efficacy in cognition models without displaying agonist activity or cholinergic toxicity
  publication-title: ACS Chem. Neurosci.
– volume: 497
  start-page: 137
  year: 2013
  end-page: 141
  ident: CR38
  article-title: Structure of active β-arrestin-1 bound to a G-protein-coupled receptor phosphopeptide
  publication-title: Nature
– volume: 61
  start-page: 55
  year: 2014
  end-page: 71
  ident: CR16
  article-title: Development of allosteric modulators of GPCRs for treatment of CNS disorders
  publication-title: Neurobiol. Dis.
– volume: 32
  start-page: 8532
  year: 2012
  end-page: 8544
  ident: CR5
  article-title: Novel allosteric agonists of M1 muscarinic acetylcholine receptors induce brain region-specific responses that correspond with behavioral effects in animal models
  publication-title: J. Neurosci.
– volume: 136
  start-page: 449
  year: 2018
  end-page: 458
  ident: CR30
  article-title: Current status of muscarinic M and M receptors as drug targets for neurodegenerative diseases
  publication-title: Neuropharmacology
– volume: 25
  start-page: 413
  year: 2004
  end-page: 422
  ident: CR47
  article-title: Historical review: a brief history and personal retrospective of seven-transmembrane receptors
  publication-title: Trends Pharmacol. Sci.
– volume: 1
  start-page: 244
  year: 2010
  end-page: 248
  ident: CR11
  article-title: Novel N-substituted benzimidazolones as potent, selective, CNS-penetrant, and orally active M mAChR agonists
  publication-title: ACS Med. Chem. Lett.
– volume: 59
  start-page: 6313
  year: 2016
  end-page: 6328
  ident: CR29
  article-title: Discovery of the potent and selective M PAM-agonist -[(3 ,4 )-3-hydroxytetrahydro-2 -pyran-4-yl]-5-methyl-4-[4-(1,3-thiazol-4-yl)benzyl]pyridine-2-carboxamide (PF-06767832): evaluation of efficacy and cholinergic side effects
  publication-title: J. Med. Chem.
– volume: 286
  start-page: 11506
  year: 2011
  end-page: 11518
  ident: CR42
  article-title: Differential G-protein-coupled receptor phosphorylation provides evidence for a signaling bar code
  publication-title: J. Biol. Chem.
– volume: 291
  start-page: 8862
  year: 2016
  end-page: 8875
  ident: CR25
  article-title: An antibody biosensor establishes the activation of the M muscarinic acetylcholine receptor during learning and memory
  publication-title: J. Biol. Chem.
– volume: 11
  start-page: 29
  year: 2019
  ident: CR53
  article-title: Cre-dependent optogenetic transgenic mice without early age-related hearing loss
  publication-title: Front. Aging Neurosci.
– volume: 93
  start-page: 645
  year: 2018
  end-page: 656
  ident: CR10
  article-title: Bitopic binding mode of an M muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes
  publication-title: Mol. Pharmacol.
– volume: 17
  start-page: 159
  year: 2006
  end-page: 165
  ident: CR24
  article-title: GRKs and β-arrestins: roles in receptor silencing, trafficking and signaling
  publication-title: Trends Endocrinol. Metab.
– volume: 89
  start-page: 683
  year: 2016
  end-page: 694
  ident: CR20
  article-title: DREADDs for neuroscientists
  publication-title: Neuron
– volume: 85
  start-page: 492
  year: 2014
  end-page: 509
  ident: CR54
  article-title: Quantification of ligand bias for clinically relevant β -adrenergic receptor ligands: implications for drug taxonomy
  publication-title: Mol. Pharmacol.
– volume: 9
  start-page: 315
  year: 1983
  end-page: 335
  ident: CR33
  article-title: Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study
  publication-title: Behav. Brain Res.
– volume: 115
  start-page: 3834
  year: 2018
  end-page: 3839
  ident: CR41
  article-title: Sortase ligation enables homogeneous GPCR phosphorylation to reveal diversity in β-arrestin coupling
  publication-title: Proc. Natl Acad. Sci. USA
– volume: 89
  start-page: 505
  year: 2016
  end-page: 520
  ident: CR36
  article-title: Distinct phosphorylation clusters determine the signaling outcome of free fatty acid receptor 4/G protein-coupled receptor 120
  publication-title: Mol. Pharmacol.
– volume: 98
  start-page: 15312
  year: 2001
  end-page: 15317
  ident: CR22
  article-title: Hyperactivity, elevated dopaminergic transmission, and response to amphetamine in M1 muscarinic acetylcholine receptor-deficient mice
  publication-title: Proc. Natl Acad. Sci. USA
– volume: 4
  start-page: ra51
  year: 2011
  ident: CR43
  article-title: Distinct phosphorylation sites on the β -adrenergic receptor establish a barcode that encodes differential functions of β-arrestin
  publication-title: Sci. Signal.
– volume: 217
  start-page: 408
  year: 1982
  end-page: 414
  ident: CR1
  article-title: The cholinergic hypothesis of geriatric memory dysfunction
  publication-title: Science
– volume: 363
  start-page: 2105
  year: 2004
  end-page: 2115
  ident: CR2
  article-title: Long-term donepezil treatment in 565 patients with Alzheimer’s disease (AD2000): randomised double-blind trial
  publication-title: Lancet
– volume: 356
  start-page: 293
  year: 2016
  end-page: 304
  ident: CR27
  article-title: Evidence for classical cholinergic toxicity associated with selective activation of M muscarinic receptors
  publication-title: J. Pharmacol. Exp. Ther.
– volume: 113
  start-page: 4524
  year: 2016
  end-page: 4529
  ident: CR23
  article-title: Mapping physiological G protein-coupled receptor signaling pathways reveals a role for receptor phosphorylation in airway contraction
  publication-title: Proc. Natl Acad. Sci. USA
– volume: 66
  start-page: 260
  year: 2004
  end-page: 267
  ident: CR26
  article-title: Cholinergic stimulation of salivary secretion studied with M and M muscarinic receptor single- and double-knockout mice
  publication-title: Mol. Pharmacol.
– volume: 8
  start-page: 41
  year: 2009
  end-page: 54
  ident: CR13
  article-title: Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders
  publication-title: Nat. Rev. Drug Discov.
– volume: 8
  start-page: 866
  year: 2017
  end-page: 883
  ident: CR15
  article-title: Diverse effects on M1 signaling and adverse effect liability within a series of M Ago-PAMs
  publication-title: ACS Chem. Neurosci.
– volume: 1
  start-page: 61
  year: 2018
  end-page: 72
  ident: CR21
  article-title: DREADD agonist 21 is an effective agonist for muscarinic-based DREADDs in vitro and in vivo
  publication-title: ACS Pharm. Transl. Sci.
– volume: 10
  year: 2019
  ident: CR40
  article-title: Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation
  publication-title: Nat. Commun.
– volume: 54
  start-page: 465
  year: 1997
  end-page: 473
  ident: CR9
  article-title: Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptoms in Alzheimer disease
  publication-title: Arch. Neurol.
– volume: 23
  start-page: 795
  year: 2006
  end-page: 812
  ident: CR52
  article-title: Circadian rhythms in heart rate, motility, and body temperature of wild-type C57 and eNOS knock-out mice under light-dark, free-run, and after time zone transition
  publication-title: Chronobiol. Int
– volume: 107
  start-page: 9440
  year: 2010
  end-page: 9445
  ident: CR45
  article-title: The M -muscarinic receptor regulates learning and memory in a receptor phosphorylation/arrestin-dependent manner
  publication-title: Proc. Natl Acad. Sci. USA
– volume: 364
  start-page: 28
  year: 2018
  end-page: 37
  ident: CR49
  article-title: An approach to discovering novel muscarinic M receptor positive allosteric modulators with potent cognitive improvement and minimized gastrointestinal dysfunction
  publication-title: J. Pharmacol. Exp. Ther.
– volume: 157
  start-page: 684
  year: 1988
  end-page: 691
  ident: CR51
  article-title: Mass measurements of inositol(1,4,5)trisphosphate in rat cerebral cortex slices using a radioreceptor assay: effects of neurotransmitters and depolarization
  publication-title: Biochem. Biophys. Res. Commun.
– volume: 365
  start-page: 602
  year: 2018
  end-page: 613
  ident: CR34
  article-title: In vitro pharmacological characterization and in vivo validation of LSN3172176 a novel M1 selective muscarinic receptor agonist tracer molecule for positron emission tomography (PET)
  publication-title: J. Pharmacol. Exp. Ther.
– volume: 60
  start-page: 6649
  year: 2017
  end-page: 6663
  ident: CR14
  article-title: Design and synthesis of γ- and δ-lactam M positive allosteric modulators (PAMs): convulsion and cholinergic toxicity of an M -selective PAM with weak agonist activity
  publication-title: J. Med. Chem.
– volume: 107
  start-page: 21181
  year: 2010
  end-page: 21186
  ident: CR44
  article-title: M -muscarinic receptor promotes insulin release via receptor phosphorylation/arrestin-dependent activation of protein kinase D1
  publication-title: Proc. Natl Acad. Sci. USA
– volume: 21
  start-page: 5239
  year: 2001
  end-page: 5250
  ident: CR48
  article-title: Hyperactivity and intact hippocampus-dependent learning in mice lacking the M muscarinic acetylcholine receptor
  publication-title: J. Neurosci.
– volume: 43
  start-page: 1763
  year: 2018
  end-page: 1771
  ident: CR7
  article-title: M -positive allosteric modulators lacking agonist activity provide the optimal profile for enhancing cognition
  publication-title: Neuropsychopharmacology
– volume: 29
  start-page: 14271
  year: 2009
  end-page: 14286
  ident: CR8
  article-title: A selective allosteric potentiator of the M muscarinic acetylcholine receptor increases activity of medial prefrontal cortical neurons and restores impairments in reversal learning
  publication-title: J. Neurosci.
– volume: 41
  start-page: 598
  year: 2016
  end-page: 610
  ident: CR6
  article-title: Potentiation of M1 muscarinic receptor reverses plasticity deficits and negative and cognitive symptoms in a schizophrenia mouse model
  publication-title: Neuropsychopharmacology
– volume: 8
  start-page: 435
  year: 2017
  end-page: 443
  ident: CR35
  article-title: Classics in chemical neuroscience: xanomeline
  publication-title: ACS Chem. Neurosci.
– volume: 127
  start-page: 45
  year: 2002
  end-page: 63
  ident: CR3
  article-title: The tolerability and safety of cholinesterase inhibitors in the treatment of dementia
  publication-title: Int. J. Clin. Pract
– volume: 291
  start-page: 8862
  year: 2016
  ident: 453_CR25
  publication-title: J. Biol. Chem.
  doi: 10.1074/jbc.M115.681726
– volume: 356
  start-page: 293
  year: 2016
  ident: 453_CR27
  publication-title: J. Pharmacol. Exp. Ther.
  doi: 10.1124/jpet.115.226910
– volume: 127
  start-page: 45
  year: 2002
  ident: 453_CR3
  publication-title: Int. J. Clin. Pract
– volume: 4
  start-page: ra51
  year: 2011
  ident: 453_CR43
  publication-title: Sci. Signal.
  doi: 10.1126/scisignal.2001707
– volume: 110
  start-page: 465
  year: 2006
  ident: 453_CR37
  publication-title: Pharmacol. Ther.
  doi: 10.1016/j.pharmthera.2005.09.008
– volume: 25
  start-page: 413
  year: 2004
  ident: 453_CR47
  publication-title: Trends Pharmacol. Sci.
  doi: 10.1016/j.tips.2004.06.006
– volume: 10
  year: 2019
  ident: 453_CR40
  publication-title: Nat. Commun.
  doi: 10.1038/s41467-019-09204-y
– volume: 1
  start-page: 61
  year: 2018
  ident: 453_CR21
  publication-title: ACS Pharm. Transl. Sci.
  doi: 10.1021/acsptsci.8b00012
– volume: 286
  start-page: 11506
  year: 2011
  ident: 453_CR42
  publication-title: J. Biol. Chem.
  doi: 10.1074/jbc.M110.154526
– volume: 1
  start-page: 244
  year: 2010
  ident: 453_CR11
  publication-title: ACS Med. Chem. Lett.
  doi: 10.1021/ml100105x
– volume: 23
  start-page: 795
  year: 2006
  ident: 453_CR52
  publication-title: Chronobiol. Int
  doi: 10.1080/07420520600827111
– volume: 60
  start-page: 6649
  year: 2017
  ident: 453_CR14
  publication-title: J. Med. Chem.
  doi: 10.1021/acs.jmedchem.7b00597
– volume: 85
  start-page: 492
  year: 2014
  ident: 453_CR54
  publication-title: Mol. Pharmacol.
  doi: 10.1124/mol.113.088880
– volume: 52
  start-page: 6366
  year: 2013
  ident: 453_CR46
  publication-title: Angew. Chem.
  doi: 10.1002/anie.201301924
– volume: 8
  start-page: 41
  year: 2009
  ident: 453_CR13
  publication-title: Nat. Rev. Drug Discov.
  doi: 10.1038/nrd2760
– volume: 89
  start-page: 683
  year: 2016
  ident: 453_CR20
  publication-title: Neuron
  doi: 10.1016/j.neuron.2016.01.040
– volume: 98
  start-page: 15312
  year: 2001
  ident: 453_CR22
  publication-title: Proc. Natl Acad. Sci. USA
  doi: 10.1073/pnas.261583798
– volume: 364
  start-page: 28
  year: 2018
  ident: 453_CR49
  publication-title: J. Pharmacol. Exp. Ther.
  doi: 10.1124/jpet.117.243774
– volume: 17
  start-page: 243
  year: 2018
  ident: 453_CR17
  publication-title: Nat. Rev. Drug Discov.
  doi: 10.1038/nrd.2017.229
– volume: 365
  start-page: 602
  year: 2018
  ident: 453_CR34
  publication-title: J. Pharmacol. Exp. Ther.
  doi: 10.1124/jpet.117.246454
– volume: 104
  start-page: 5163
  year: 2007
  ident: 453_CR19
  publication-title: Proc. Natl Acad. Sci. USA
  doi: 10.1073/pnas.0700293104
– volume: 8
  start-page: 435
  year: 2017
  ident: 453_CR35
  publication-title: ACS Chem. Neurosci.
  doi: 10.1021/acschemneuro.7b00001
– volume: 217
  start-page: 408
  year: 1982
  ident: 453_CR1
  publication-title: Science
  doi: 10.1126/science.7046051
– volume: 16
  start-page: 721
  year: 2013
  ident: 453_CR12
  publication-title: Int. J. Neuropsychopharmacol.
  doi: 10.1017/S1461145712000752
– volume: 136
  start-page: 449
  year: 2018
  ident: 453_CR30
  publication-title: Neuropharmacology
  doi: 10.1016/j.neuropharm.2018.01.028
– volume: 260
  start-page: 45
  year: 2016
  ident: 453_CR32
  publication-title: J. Neurosci. Methods
  doi: 10.1016/j.jneumeth.2015.03.009
– volume: 363
  start-page: 2105
  year: 2004
  ident: 453_CR2
  publication-title: Lancet
  doi: 10.1016/S0140-6736(04)16499-4
– volume: 43
  start-page: 1763
  year: 2018
  ident: 453_CR7
  publication-title: Neuropsychopharmacology
  doi: 10.1038/s41386-018-0033-9
– volume: 9
  start-page: 2274
  year: 2018
  ident: 453_CR50
  publication-title: ACS Chem. Neurosci.
  doi: 10.1021/acschemneuro.8b00131
– volume: 21
  start-page: 5239
  year: 2001
  ident: 453_CR48
  publication-title: J. Neurosci.
  doi: 10.1523/JNEUROSCI.21-14-05239.2001
– volume: 59
  start-page: 6313
  year: 2016
  ident: 453_CR29
  publication-title: J. Med. Chem.
  doi: 10.1021/acs.jmedchem.6b00544
– volume: 9
  start-page: 315
  year: 1983
  ident: 453_CR33
  publication-title: Behav. Brain Res.
  doi: 10.1016/0166-4328(83)90136-5
– volume: 37
  start-page: 1015
  year: 1996
  ident: 453_CR31
  publication-title: Epilepsia
  doi: 10.1111/j.1528-1157.1996.tb00541.x
– volume: 127
  start-page: 487
  year: 2017
  ident: 453_CR4
  publication-title: J. Clin. Invest.
  doi: 10.1172/JCI87526
– volume: 11
  start-page: 29
  year: 2019
  ident: 453_CR53
  publication-title: Front. Aging Neurosci.
  doi: 10.3389/fnagi.2019.00029
– volume: 66
  start-page: 260
  year: 2004
  ident: 453_CR26
  publication-title: Mol. Pharmacol.
  doi: 10.1124/mol.66.2.260
– volume: 107
  start-page: 9440
  year: 2010
  ident: 453_CR45
  publication-title: Proc. Natl Acad. Sci. USA
  doi: 10.1073/pnas.0914801107
– volume: 75
  start-page: 577
  year: 2009
  ident: 453_CR18
  publication-title: Mol. Pharmacol.
  doi: 10.1124/mol.108.052886
– volume: 8
  start-page: 866
  year: 2017
  ident: 453_CR15
  publication-title: ACS Chem. Neurosci.
  doi: 10.1021/acschemneuro.6b00429
– volume: 41
  start-page: 598
  year: 2016
  ident: 453_CR6
  publication-title: Neuropsychopharmacology
  doi: 10.1038/npp.2015.189
– volume: 115
  start-page: 3834
  year: 2018
  ident: 453_CR41
  publication-title: Proc. Natl Acad. Sci. USA
  doi: 10.1073/pnas.1722336115
– volume: 107
  start-page: 21181
  year: 2010
  ident: 453_CR44
  publication-title: Proc. Natl Acad. Sci. USA
  doi: 10.1073/pnas.1011651107
– volume: 54
  start-page: 465
  year: 1997
  ident: 453_CR9
  publication-title: Arch. Neurol.
  doi: 10.1001/archneur.1997.00550160091022
– volume: 29
  start-page: 14271
  year: 2009
  ident: 453_CR8
  publication-title: J. Neurosci.
  doi: 10.1523/JNEUROSCI.3930-09.2009
– volume: 93
  start-page: 645
  year: 2018
  ident: 453_CR10
  publication-title: Mol. Pharmacol.
  doi: 10.1124/mol.118.111872
– volume: 11
  start-page: S16
  year: 1997
  ident: 453_CR28
  publication-title: Alzheimer Dis. Assoc. Disord.
  doi: 10.1097/00002093-199703000-00004
– volume: 113
  start-page: 4524
  year: 2016
  ident: 453_CR23
  publication-title: Proc. Natl Acad. Sci. USA
  doi: 10.1073/pnas.1521706113
– volume: 157
  start-page: 684
  year: 1988
  ident: 453_CR51
  publication-title: Biochem. Biophys. Res. Commun.
  doi: 10.1016/S0006-291X(88)80304-8
– volume: 17
  start-page: 159
  year: 2006
  ident: 453_CR24
  publication-title: Trends Endocrinol. Metab.
  doi: 10.1016/j.tem.2006.03.008
– volume: 170
  start-page: 457
  year: 2017
  ident: 453_CR39
  publication-title: Cell
  doi: 10.1016/j.cell.2017.07.002
– volume: 32
  start-page: 8532
  year: 2012
  ident: 453_CR5
  publication-title: J. Neurosci.
  doi: 10.1523/JNEUROSCI.0337-12.2012
– volume: 497
  start-page: 137
  year: 2013
  ident: 453_CR38
  publication-title: Nature
  doi: 10.1038/nature12120
– volume: 61
  start-page: 55
  year: 2014
  ident: 453_CR16
  publication-title: Neurobiol. Dis.
  doi: 10.1016/j.nbd.2013.09.013
– volume: 89
  start-page: 505
  year: 2016
  ident: 453_CR36
  publication-title: Mol. Pharmacol.
  doi: 10.1124/mol.115.101949
– reference: 32080631 - Nat Chem Biol. 2020 Mar;16(3):226-227. doi: 10.1038/s41589-020-0468-2.
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Snippet Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer’s disease (AD), are associated with low efficacy and adverse effects. M1...
Cholinesterase inhibitors, the current frontline symptomatic treatment for Alzheimer's disease (AD), are associated with low efficacy and adverse effects. M1...
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StartPage 240
SubjectTerms 631/154
631/154/436
631/378/340
631/92/96
Acetylcholine receptors (muscarinic)
Acetylcholinesterase - metabolism
Alzheimer Disease - drug therapy
Alzheimer's disease
Animal models
Animals
Anxiety
Biochemical Engineering
Biochemistry
Bioorganic Chemistry
Cell Biology
Chemistry
Chemistry and Materials Science
Chemistry/Food Science
Cholinergic Agents - pharmacology
Cholinergics
Cholinesterase
Cholinesterase inhibitors
Cholinesterase Inhibitors - metabolism
Cholinesterase Inhibitors - pharmacology
Disease Models, Animal
Drug Design
Drug development
Epilepsy
Female
G protein-coupled receptors
Gene Knock-In Techniques
Ligands
Locomotion
Male
Mapping
Medical treatment
Mice
Mice, Inbred C57BL
Mutants
Neurodegenerative diseases
Phosphorylation
Proteins
Receptor, Muscarinic M1 - genetics
Receptor, Muscarinic M1 - metabolism
Receptors
Seizures
Side effects
Signaling
Therapeutic applications
Title Biased M1-muscarinic-receptor-mutant mice inform the design of next-generation drugs
URI https://link.springer.com/article/10.1038/s41589-019-0453-9
https://www.ncbi.nlm.nih.gov/pubmed/32080630
https://www.proquest.com/docview/2359368774
https://www.proquest.com/docview/2476773635
https://www.proquest.com/docview/2386281442
https://pubmed.ncbi.nlm.nih.gov/PMC7616160
Volume 16
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