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M1 receptor

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Target id: 13

Nomenclature: M1 receptor

Family: Acetylcholine receptors (muscarinic)

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 460 11q12.3 CHRM1 cholinergic receptor muscarinic 1 12,107
Mouse 7 460 19 A Chrm1 cholinergic receptor, muscarinic 1, CNS 91,122
Rat 7 460 1q43 Chrm1 cholinergic receptor, muscarinic 1 71,105,130,140
Previous and Unofficial Names Click here for help
M1 muscarinic acetylcholine receptor | Chrm-1 | M1R | cholinergic receptor, muscarinic 1 | cholinergic receptor | cholinergic receptor, muscarinic 1, CNS
Database Links Click here for help
Specialist databases
GPCRdb acm1_human (Hs), acm1_mouse (Mm), acm1_rat (Rn)
Other databases
Alphafold P11229 (Hs), P12657 (Mm), P08482 (Rn)
ChEMBL Target CHEMBL216 (Hs), CHEMBL3733 (Mm), CHEMBL276 (Rn)
DrugBank Target P11229 (Hs)
Ensembl Gene ENSG00000168539 (Hs), ENSMUSG00000032773 (Mm), ENSRNOG00000018385 (Rn)
Entrez Gene 1128 (Hs), 12669 (Mm), 25229 (Rn)
Human Protein Atlas ENSG00000168539 (Hs)
KEGG Gene hsa:1128 (Hs), mmu:12669 (Mm), rno:25229 (Rn)
OMIM 118510 (Hs)
Pharos P11229 (Hs)
RefSeq Nucleotide NM_000738 (Hs), NM_007698 (Mm), NM_080773 (Rn)
RefSeq Protein NP_000729 (Hs), NP_031724 (Mm), NP_542951 (Rn)
SynPHARM 82388 (in complex with tiotropium)
UniProtKB P11229 (Hs), P12657 (Mm), P08482 (Rn)
Wikipedia CHRM1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Crystal structure of the human M1 muscarinic acetylcholine receptor bound to antagonist tiotropium.
PDB Id:  5CXV
Ligand:  tiotropium
Resolution:  2.7Å
Species:  Human
References:  139
Natural/Endogenous Ligands Click here for help
acetylcholine

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]iperoxo Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Agonist 8.7 pKd 120
⤷ pKd 8.7 [120]
NNC 11-1585 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 9.9 pKi 26
⤷ pKi 9.9 [26]
NNC 11-1607 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.6 pKi 26
⤷ pKi 8.6 [26]
pentylthio-TZTP Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.6 pKi 64
⤷ pKi 8.6 [64]
NNC 11-1314 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.4 pKi 26
⤷ pKi 7.4 [26]
xanomeline Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 6.7 – 7.9 pKi 27,109,149,161
⤷ pKi 6.7 – 7.9 [27,109,149,161]
sabcomeline Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 6.7 pKi 161
⤷ pKi 6.7 [161]
arecaidine propargyl ester Small molecule or natural product Click here for species-specific activity table Hs Full agonist 6.4 pKi 64
⤷ pKi 6.4 [64]
LY593093 Small molecule or natural product Hs Partial agonist 6.2 pKi 151
⤷ pKi 6.2 [151]
AC-42 Small molecule or natural product Hs Full agonist 6.2 pKi 75
⤷ pKi 6.2 [75]
oxotremorine Small molecule or natural product Click here for species-specific activity table Rn Partial agonist 6.0 pKi 93
⤷ pKi 6.0 [93]
arecoline Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.7 pKi 64,103,114
⤷ pKi 5.7 [64,103,114]
oxotremorine-M Small molecule or natural product Rn Full agonist 5.6 pKi 93
⤷ pKi 5.6 [93]
oxotremorine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.5 pKi 64,114
⤷ pKi 5.5 [64,114]
cevimeline Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 5.3 pKi 84
⤷ pKi 5.3 (Ki 4.85x10-6 M) [84]
Description: Displacement of [3H]QNB from cloned receptor.
arecoline Small molecule or natural product Rn Partial agonist 5.3 pKi 93
⤷ pKi 5.3 [93]
McN-A-343 Small molecule or natural product Click here for species-specific activity table Rn Partial agonist 5.1 pKi 93
⤷ pKi 5.1 [93]
oxotremorine-M Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.1 pKi 64
⤷ pKi 5.1 [64]
pilocarpine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 5.1 pKi 64,114
⤷ pKi 5.1 [64,114]
McN-A-343 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 4.8 – 5.2 pKi 114
⤷ pKi 4.8 – 5.2 [114]
acetylcholine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Rn Full agonist 5.0 pKi 25
⤷ pKi 5.0 [25]
pilocarpine Small molecule or natural product Approved drug Ligand has a PDB structure Rn Partial agonist 4.9 pKi 93
⤷ pKi 4.9 [93]
milameline Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 4.8 pKi 161
⤷ pKi 4.8 [161]
acetylcholine Small molecule or natural product Click here for species-specific activity table Ligand is endogenous in the given species Ligand has a PDB structure Hs Full agonist 4.3 – 4.9 pKi 64,68
⤷ pKi 4.3 – 4.9 [64,68]
methylfurmethide Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.6 pKi 64
⤷ pKi 4.6 [64]
(-)-YM796 Small molecule or natural product Hs Partial agonist 4.3 – 4.8 pKi 152
⤷ pKi 4.3 – 4.8 [152]
(±)YM796 Small molecule or natural product Hs Partial agonist 4.1 – 4.7 pKi 152
⤷ pKi 4.1 – 4.7 [152]
carbachol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 3.2 – 5.3 pKi 27,64,161
⤷ pKi 3.2 – 5.3 [27,64,161]
furtrethonium Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.1 pKi 64
⤷ pKi 4.1 [64]
bethanechol Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 4.0 pKi 64,114
⤷ pKi 4.0 [64,114]
carbachol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Full agonist 3.9 pKi 25
⤷ pKi 3.9 [25]
bethanechol Small molecule or natural product Approved drug Rn Full agonist 3.7 pKi 93
⤷ pKi 3.7 [93]
AZD6088 Small molecule or natural product Primary target of this compound Hs Partial agonist 8.3 pEC50 97
⤷ pEC50 8.3 (EC50 5x10-9 M) [97]
methacholine Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Rn Agonist 6.4 pEC50 104,114
⤷ pEC50 6.4 (EC50 4x10-7 M) [104,114]
(+)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.4 pEC50 35
⤷ pEC50 5.4 [35]
(-)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.0 pEC50 35
⤷ pEC50 5.0 [35]
[11C]butylthio-TZTP Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist - - 38
⤷ [38]
[11C]xanomeline Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist - - 38
⤷ [38]
iperoxo Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - - 120
⤷ [120]
[3H]acetylcholine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Ligand has a PDB structure Hs Agonist - -
⤷
SPP1 Small molecule or natural product N/A Agonist - - 16
⤷ [16]
View species-specific agonist tables
Agonist Comments
Please consult references [17,79,114,147,158] for further details of the activity of some of the ligands in this list.

Pilocarpine has been found to be a partial agonist [79,114,158] as well as a full agonist [147] at the M1 receptor; oxotremorine has also been found to be a partial agonist [79,114,147] as well as a full agonist [114] at the M1 receptor.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]QNB Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 10.6 – 10.8 pKd 63,107
⤷ pKd 10.6 – 10.8 (Kd 2.51x10-11 – 1.58x10-11 M) [63,107]
Cy3B-telenzepine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Hs Antagonist 10.5 pKd 56
⤷ pKd 10.5 [56]
[3H]N-methyl scopolamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.4 – 10.3 pKd 23,27-28,58,64-66,69,77
⤷ pKd 9.4 – 10.3 (Kd 4.2x10-10 – 5x10-11 M) [23,27-28,58,64-66,69,77]
[3H]N-methyl scopolamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Antagonist 9.7 pKd 25,147
⤷ pKd 9.7 [25,147]
biperiden Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.3 pKd 11
⤷ pKd 9.3 (Kd 4.8x10-10 M) [11]
Alexa-488-telenzepine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Hs Antagonist 9.3 pKd 56
⤷ pKd 9.3 [56]
[3H]darifenacin Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.8 pKd 126
⤷ pKd 8.8 [126]
[3H]pirenzepine Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 7.9 pKd 24,119,143,150
⤷ pKd 7.9 (Kd 1.4x10-8 M) [24,119,143,150]
[3H]pirenzepine Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist 7.7 – 7.9 pKd 37,51
⤷ pKd 7.7 – 7.9 [37,51]
otenzepad Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.2 pKd 36
⤷ pKd 6.2 [36]
tiotropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.6 – 10.7 pKi 33,111,135,137
⤷ pKi 9.6 – 10.7 [33,111,135,137]
N-methyl scopolamine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.9 pKi 40
⤷ pKi 9.9 [40]
umeclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.8 pKi 73,118
⤷ pKi 9.8 (Ki 1.6x10-10 M) [73,118]
propantheline Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.7 pKi 60
⤷ pKi 9.7 [60]
ipratropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.3 – 9.8 pKi 58,111
⤷ pKi 9.3 – 9.8 [58,111]
[3H](+)telenzepine Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist 9.4 pKi 37
⤷ pKi 9.4 [37]
revefenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.4 pKi 55
⤷ pKi 9.4 (Ki 4.17x10-10 M) [55]
Description: Determined from a radioligand binding assay using membranes from CHO‐K1 cells expressing the hM1 receptor, and displacement of [3H]NMS tracer.
atropine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 9.0 – 9.7 pKi 18,25,67
⤷ pKi 9.0 – 9.7 [18,25,67]
4-DAMP Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.3 pKi 34
⤷ pKi 9.3 [34]
dicyclomine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.1 pKi 5
⤷ pKi 9.1 (Ki 8.3x10-10 M) [5]
atropine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.5 – 9.6 pKi 27,40,58,60,107,126
⤷ pKi 8.5 – 9.6 [27,40,58,60,107,126]
benzatropine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 9.0 pKi 99
⤷ pKi 9.0 (Ki 9.5x10-10 M) [99]
Description: Displacement binding experiment using homogenised rat caudate putamen.
darifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.9 – 9.1 pKi 45,58,125
⤷ pKi 8.9 – 9.1 [45,58,125]
scopolamine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 9.0 pKi 30,60
⤷ pKi 9.0 [30,60]
4-DAMP Small molecule or natural product Click here for species-specific activity table Rn Antagonist 8.9 pKi 67
⤷ pKi 8.9 [67]
trihexyphenidyl Small molecule or natural product Approved drug Primary target of this compound Hs Antagonist 8.9 pKi 5
⤷ pKi 8.9 (Ki 1.35x10-9 M) [5]
tripitramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.8 pKi 87
⤷ pKi 8.8 [87]
silahexocyclium Small molecule or natural product Rn Antagonist 8.7 pKi 18
⤷ pKi 8.7 [18]
hexocyclium Small molecule or natural product Rn Antagonist 8.6 pKi 18
⤷ pKi 8.6 [18]
oxybutynin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.6 pKi 32,125
⤷ pKi 8.6 (Ki 2.4x10-9 M) [32,125]
ethopropazine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 8.5 pKi 19
⤷ pKi 8.5 (Ki 3.1x10-9 M) [19]
Description: Displacement of [H]QNB binding in rat forebrain brain homogenate.
tolterodine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.4 – 8.5 pKi 45,125
⤷ pKi 8.4 – 8.5 [45,125]
oxybutynin Small molecule or natural product Approved drug Rn Antagonist 8.2 pKi 98
⤷ pKi 8.2 [98]
hexahydrodifenidol Small molecule or natural product Rn Antagonist 8.0 pKi 18
⤷ pKi 8.0 [18]
solifenacin Small molecule or natural product Approved drug Rn Antagonist 8.0 pKi 98
⤷ pKi 8.0 [98]
pirenzepine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.6 – 8.3 pKi 18,34,54,60,66,157
⤷ pKi 7.6 – 8.3 [18,34,54,60,66,157]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 7.8 – 7.9 pKi 18,67
⤷ pKi 7.8 – 7.9 [18,67]
amitriptyline Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.8 pKi 129
⤷ pKi 7.8 (Ki 1.47x10-8 M) [129]
methoctramine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.8 pKi 18
⤷ pKi 7.8 [18]
VU0255035 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.8 pKi 123
⤷ pKi 7.8 (Ki 1.487x10-8 M) [123]
dosulepin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.7 pKi 129
⤷ pKi 7.7 (Ki 1.8x10-8 M) [129]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.7 pKi 36
⤷ pKi 7.7 [36]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.4 – 7.9 pKi 18,67
⤷ pKi 7.4 – 7.9 [18,67]
solifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.6 pKi 61,125
⤷ pKi 7.6 [61,125]
AFDX384 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.5 pKi 34
⤷ pKi 7.5 [34]
p-F-HHSiD Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.1 – 7.8 pKi 36,60
⤷ pKi 7.1 – 7.8 [36,60]
muscarinic toxin 1 Peptide Click here for species-specific activity table Hs Antagonist 7.3 – 7.6 pKi 40,52
⤷ pKi 7.3 – 7.6 [40,52]
guanylpirenzepine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.3 – 7.6 pKi 3,146
⤷ pKi 7.3 – 7.6 [3,146]
AQ-RA 741 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.2 – 7.5 pKi 34,45
⤷ pKi 7.2 – 7.5 [34,45]
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Antagonist 7.1 pKi 66
⤷ pKi 7.1 [66]
droxidopa Small molecule or natural product Approved drug Hs Antagonist 7.1 pKi 30
⤷ pKi 7.1 [30]
BODIPY-pirenzepine Small molecule or natural product Ligand is labelled Hs Antagonist 7.0 pKi 62
⤷ pKi 7.0 [62]
methoctramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.6 – 7.3 pKi 34,36,54,126
⤷ pKi 6.6 – 7.3 [34,36,54,126]
himbacine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.7 – 7.1 pKi 34,66,95
⤷ pKi 6.7 – 7.1 [34,66,95]
(S)-dimetindene Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.7 pKi 21
⤷ pKi 6.7 (Ki 1.906x10-7 M) [21]
Description: Binding to hM1 receptors expressed in CHO cells.
muscarinic toxin 2 Peptide Click here for species-specific activity table Hs Antagonist 6.4 pKi 52
⤷ pKi 6.4 [52]
otenzepad Small molecule or natural product Click here for species-specific activity table Rn Antagonist 5.9 – 6.3 pKi 18,67
⤷ pKi 5.9 – 6.3 [18,67]
lithocholylcholine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 5.6 pKi 25
⤷ pKi 5.6 [25]
ML381 Small molecule or natural product Click here for species-specific activity table Hs Antagonist <5.0 pKi 42
⤷ pKi <5.0 (Ki >1x10-5 M) [42]
aclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 10.1 – 10.2 pIC50 111,137
⤷ pIC50 10.1 – 10.2 [111,137]
glycopyrrolate Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.6 – 10.1 pIC50 131,135
⤷ pIC50 9.6 – 10.1 [131,135]
Description: Assay uses glycopyrronium bromide
solifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.2 pIC50 110
⤷ pIC50 7.2 (IC50 6.35x10-8 M) [110]
[18F](R,R)-quinuclidinyl-4-fluoromethyl-benzilate Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist - - 70
⤷ [70]
View species-specific antagonist tables
Antagonist Comments
Recombinant MT7 (rMT7) is often used for bioassays due to the limited availability of the M1 muscarinic receptor-selective mamba toxin MT7 or m1-toxin 1 (rMT7 has comparable affinity for M1 [100]).

Biperiden is an approved drug antagonist of muscarinic acetylcholine receptors. We have tagged the M1 subtype as the drug's primary target as affinity is 10-fold higher at this receptor subtype [11]. Ethopropazine appears to have highest affinity for the M1 subtype in rat brain homegenates [19], so the M1 receptor is the likely primary human target of this drug.
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
benzoquinazolinone 12 Small molecule or natural product Hs Positive 6.6 pKB 1
⤷ pKB 6.6 [1]
BQCA Small molecule or natural product Hs Positive 4.0 – 4.8 pKB 1-2,22,86
⤷ pKB 4.0 – 4.8 [1-2,22,86]
KT 5720 Small molecule or natural product Click here for species-specific activity table Hs Positive 6.4 pKd 81
⤷ pKd 6.4 (Kd 3.98x10-7 M) [81]
staurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 5.9 pKd 81
⤷ pKd 5.9 [81]
Gö 7874 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.8 pKd 81
⤷ pKd 5.8 [81]
WIN 51,708 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.8 pKd 82
⤷ pKd 5.8 [82]
KT 5823 Small molecule or natural product Click here for species-specific activity table Hs Positive 5.7 pKd 81
⤷ pKd 5.7 [81]
WIN 62,577 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.5 pKd 82
⤷ pKd 5.5 [82]
brucine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.5 – 5.8 pKd 10,64,80
⤷ pKd 4.5 – 5.8 (Kd 3x10-5 – 1.78x10-6 M) [10,64,80]
K-252a Small molecule or natural product Click here for species-specific activity table Hs Positive 5.1 pKd 81
⤷ pKd 5.1 [81]
vinburnine Small molecule or natural product Click here for species-specific activity table Hs Neutral 5.1 pKd 64
⤷ pKd 5.1 [64]
alcuronium Small molecule or natural product Click here for species-specific activity table Hs Negative 5.0 pKd 64
⤷ pKd 5.0 [64]
strychnine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Neutral 4.9 – 5.0 pKd 64,77
⤷ pKd 4.9 – 5.0 [64,77]
strychnine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Negative 4.9 pKd 77
⤷ pKd 4.9 [77]
vincamine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.8 pKd 64
⤷ pKd 4.8 [64]
brucine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.5 pKd 80
⤷ pKd 4.5 [80]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.4 pKd 80
⤷ pKd 4.4 [80]
N-chloromethyl-brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.1 pKd 80
⤷ pKd 4.1 [80]
thiochrome Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.1 pKd 78
⤷ pKd 4.1 [78]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Neutral 3.2 pKd 80
⤷ pKd 3.2 [80]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Positive 3.2 pKd 80
⤷ pKd 3.2 [80]
muscarinic toxin 7 Peptide Click here for species-specific activity table Hs Negative 11.0 – 11.1 pKi 40,100,102
⤷ pKi 11.0 – 11.1 [40,100,102]
AC-42 Small molecule or natural product Hs Negative 6.2 pKi 75
⤷ pKi 6.2 [75]
T440 Small molecule or natural product Rn Positive 8.2 pEC50 141
⤷ pEC50 8.2 (EC50 5.9x10-9 M) [141]
T440 Small molecule or natural product Hs Positive 8.2 pEC50 141
⤷ pEC50 8.2 (EC50 6.3x10-9 M) [141]
Description: Determined in CHO-K1 cells transfected with the human M1 receptor.
T532 Small molecule or natural product Hs Positive 8.0 – 8.1 pEC50 113
⤷ pEC50 8.0 – 8.1 (EC50 1x10-8 – 8x10-9 M) [113]
Description: PAM potency determined in M1 receptor-expressing CHO cells
PF-06767832 Small molecule or natural product Primary target of this compound Hs Positive 7.2 pEC50 31
⤷ pEC50 7.2 (EC50 6x10-8 M) [31]
Description: FLIPR calcium mobilisation assay
VU0486846 Small molecule or natural product Hs Positive 6.5 pEC50 115
⤷ pEC50 6.5 (EC50 3.1x10-7 M) [115]
Description: PAM potency
ML169 Small molecule or natural product Hs Positive 5.9 pEC50 138
⤷ pEC50 5.9 (EC50 1.38x10-6 M) [138]
VU0486846 Small molecule or natural product Hs Agonist 5.4 pEC50 115
⤷ pEC50 5.4 (EC50 4x10-6 M) [115]
Description: Agonist potency
VU0119498 Small molecule or natural product Click here for species-specific activity table Hs Positive 5.2 pEC50 15
⤷ pEC50 5.2 (EC50 6.04x10-6 M) [15]
clozapine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Positive 7.9 pIC50 133
⤷ pIC50 7.9 [133]
clozapine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Positive 7.7 pIC50 128
⤷ pIC50 7.7 [128]
N-desmethylclozapine Small molecule or natural product Hs Positive 7.3 pIC50 133
⤷ pIC50 7.3 [133]
N-desmethylclozapine Small molecule or natural product Rn Positive 6.8 pIC50 128
⤷ pIC50 6.8 [128]
AC-260584 Small molecule or natural product Rn Positive 5.9 pIC50 128
⤷ pIC50 5.9 [128]
tacrine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Mm Negative 5.7 pIC50 127
⤷ pIC50 5.7 (IC50 2x10-6 M) [127]
VU0090157 Small molecule or natural product Hs Positive - - 90
⤷ [90]
VU0029767 Small molecule or natural product Hs Positive - - 90
⤷ [90]
T‐495 Small molecule or natural product Hs Positive - - 88
⤷ [88]
MK-7622 Small molecule or natural product Hs Positive - - 8
⤷ [8]
View species-specific allosteric modulator tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
References:  9,14,106,117
Tissue Distribution Click here for help
Esophageal smooth muscle.
Species:  Human
Technique:  Radioligand binding.
References:  112
Bladder.
Species:  Human
Technique:  RT-PCR.
References:  142
CNS: cerebral cortex, basal ganglia, limbic areas.
Species:  Human
Technique:  Radioligand binding.
References:  29
Vestibular system.
Species:  Human
Technique:  RT-PCR.
References:  145
CNS: forebrain.
Species:  Mouse
Technique:  immunocytochemistry.
References:  59
CNS: cerbral cortex, corpus striatum, hippocampus, thalamus.
Species:  Mouse
Technique:  Radioligand binding.
References:  101
CNS: cerebral cortex, hippocampus, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum.
Species:  Rat
Technique:  Immunoprecipitation.
References:  163
Vestibular system.
Species:  Rat
Technique:  RT-PCR.
References:  145
CNS: caudate putamen, nucleus accumbens, olfactory tubercle.
Species:  Rat
Technique:  in situ hybridisation.
References:  153
CNS: pons.
Species:  Rat
Technique:  Radioligand binding.
References:  6
Heart: intrinsic neurons.
Species:  Rat
Technique:  in situ hybridisation.
References:  53
CNS: hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  83
CNS: cranial nerve nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  144
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Measurement of PI levels in mouse Y1 adrenal cells transfected with the mouse M1 receptor.
Species:  Mouse
Tissue:  Y1 adrenal cells.
Response measured:  Stimulation of PI hydrolysis.
References:  122
Measurement of PI hydrolysis, Ca2+ mobilisation and [3H]arachidonic acid release in A9 L cells transfected with the human M1 receptor.
Species:  Human
Tissue:  A9 L cells.
Response measured:  Stimulation of PI hydrolysis, Ca2+ mobilisation and [3H]arachidonic acid release.
References:  7
Measurement of PI hydrolysis in CHO cells transfected with the human M1 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Stimulation of PI hydrolysis.
References:  26
Measurement of ERK1/2 activity in hippocampal cells endogenously expressing the M1 receptor.
Species:  Rat
Tissue:  Post-ischemic hippocampus.
Response measured:  Increase in ERK1/2 activity.
References:  136
Measurement of activation of ERK1/2 in PC12D cells endogeneously expressing the M1 receptor.
Species:  Rat
Tissue:  Neuronal PC12D cells.
Response measured:  Activation of ERK1/2.
References:  47
Measurement of activation of neuronal nitric oxide synthetase in chinese hamster overy cells transfected with the M1 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Activation of nitric oxide synthetase.
References:  148
Measurement of ERK1/2 activity in COS-7 cells transfected with the human M2 receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Increase in ERK1/2 activity.
References:  116
Measurement of GIRK channel activity in Xenopus oocytes transfected with the human M1 receptor.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Inhibition of GIRK channels.
References:  57
Measurement of the effects of a ligand on the level, or rate, of binding of GTPγ35S to membranes.
Species:  Human
Tissue:  CHO cell membranes.
Response measured:  The binding of GTPγ35S to G proteins coupled to the receptor.
References:  10,76-79,81-82
Measurement of the effects of a ligand on the rate of hydrolysis of GTP by G proteins in membranes.
Species:  Human
Tissue:  CHO cells.
Response measured:  Generation of 32Pi from [γ-32P]GTP.
References:  79
Physiological Functions Click here for help
Vasodilation.
Species:  Rat
Tissue:  Lung.
References:  159
Bronchoconstriction.
Species:  Human
Tissue:  In vivo.
References:  74
Modulation of NMDA receptor-meditated excitatory synaptic transmission.
Species:  Rat
Tissue:  Hippocampal CA1 pyramidal cells.
References:  89
Regulation of circadian rhythms.
Species:  Rat
Tissue:  Hypothalamic suprachiasmatic nucleus.
References:  46
Automaticity of the heart.
Species:  Mouse
Tissue:  Heart.
References:  160
Autoreceptor: modulation of ACh release.
Species:  Rat
Tissue:  Basal forebrain slices.
References:  134
Autoreceptor: modulation of ACh release.
Species:  Human
Tissue:  Neocortex slices.
References:  39
Stimulation of water consumption.
Species:  Rat
Tissue:  In vivo.
References:  108
Hypothermia.
Species:  Rat
Tissue:  In vivo.
References:  121
Spinal analgesia.
Species:  Rat
Tissue:  In vivo.
References:  44
Memory function.
Species:  Rat
Tissue:  In vivo.
References:  94
Stimulation of urination.
Species:  Rat
Tissue:  In vivo.
References:  72
Physiological Consequences of Altering Gene Expression Click here for help
M1 receptor knockout mice exhibit reduced salivary flow.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  41
Lung slices from M1 receptor knockout mice exhibit increased agonist-induced bronchoconstriction compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  132
M1 receptor knockout mice exhibit an increased tidal volume of the lung at rest.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  13
M1 receptor knockout mice exhibit reduced seizure activity in the pilocarpine model of epilepsy.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  50
M1 receptor knockout mice exhibit loss of regulation of M-current potassium channel activity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  50
M1 receptor knockout mice exhibit a loss of the positive chronotropic and inotropic responses.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  49
M1 receptor knockout mice exhibit increased locomotor activity and hyperactivity under stress.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  96
M1 receptor knockout mice exhibit increased dopamine levels in the striatum and increased locomotor activity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  43
M1 receptor knockout mice showed normal or even enhanced memory for tasks that involve matching-to-sample problems but significant impairments in non-matching-to-sample working memory and consolidation.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  4
M1 receptor knockout mice exhibit disrupted tonotopic organisation and frequency tuning in the auditory cortex.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  164-165
M1 receptor knockout mice exhibit reduced gastric pepsinogen secretion.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  162
Hippocampal slices from M1 receptor knockout mice do not exhibit carbachol-induced enhancement of LTP of excitatory synaptic transmission as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  124
M1 receptor knockout mice exhibit reduced carbachol-stimulated ion secretion in the colon compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  48
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Chrm1tm1Nmn Chrm1tm1Nmn/Chrm1tm1Nmn
B6.129X1-Chrm1		 MGI:88396  MP:0004631 abnormal auditory cortex morphology PMID: 15721569 
Chrm1tm1Nmn Chrm1tm1Nmn/Chrm1tm1Nmn
B6.129X1-Chrm1		 MGI:88396  MP:0004788 abnormal auditory cortex tonotopy PMID: 15721569 
Chrm1tm1Nmn Chrm1tm1Nmn/Chrm1tm1Nmn
B6.129X1-Chrm1		 MGI:88396  MP:0004996 abnormal CNS synapse formation PMID: 15721569 
Chrm1tm1Jwe|Chrm4tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MGI:88399  MP:0002206 abnormal CNS synaptic transmission PMID: 15919709 
Chrm1tm2.1Stl|Emx1tm1.1(cre)Ito Chrm1tm2.1Stl/Chrm1tm2.1Stl,Emx1tm1.1(cre)Ito/0
involves: 129P2/OlaHsd		 MGI:88396  MGI:95387  MP:0002910 abnormal excitatory postsynaptic currents PMID: 20080609 
Chrm1tm2.1Stl|Tg(Grik4-cre)G32-4Stl Chrm1tm2.1Stl/Chrm1tm2.1Stl,Tg(Grik4-cre)G32-4Stl/0
involves: 129P2/OlaHsd * C57BL/6		 MGI:2448783  MGI:88396  MP:0002910 abnormal excitatory postsynaptic currents PMID: 20080609 
Chrm1tm1Stl Chrm1tm1Stl/Chrm1tm1Stl
involves: C57BL/6		 MGI:88396  MP:0002912 abnormal excitatory postsynaptic potential PMID: 16290192 
Chrm1tm1Kano Chrm1tm1Kano/Chrm1tm1Kano
involves: 129X1/SvJ * C57BL/6		 MGI:88396  MP:0002945 abnormal inhibitory postsynaptic currents PMID: 12859343 
Chrm1tm1Kano|Chrm3tm1Mmt Chrm1tm1Kano/Chrm1tm1Kano,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88396  MGI:88398  MP:0002945 abnormal inhibitory postsynaptic currents PMID: 12859343 
Chrm1tm2.1Stl|Emx1tm1.1(cre)Ito Chrm1tm2.1Stl/Chrm1tm2.1Stl,Emx1tm1.1(cre)Ito/0
involves: 129P2/OlaHsd		 MGI:88396  MGI:95387  MP:0001898 abnormal long term depression PMID: 20080609 
Chrm1tm2.1Stl|Tg(Grik4-cre)G32-4Stl Chrm1tm2.1Stl/Chrm1tm2.1Stl,Tg(Grik4-cre)G32-4Stl/0
involves: 129P2/OlaHsd * C57BL/6		 MGI:2448783  MGI:88396  MP:0001898 abnormal long term depression PMID: 20080609 
Chrm1tm2.1Stl|Emx1tm1.1(cre)Ito Chrm1tm2.1Stl/Chrm1tm2.1Stl,Emx1tm1.1(cre)Ito/0
involves: 129P2/OlaHsd		 MGI:88396  MGI:95387  MP:0004753 abnormal miniature excitatory postsynaptic currents PMID: 20080609 
Chrm1tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MP:0002272 abnormal nervous system electrophysiology PMID: 11856534 
Chrm1tm1Kano|Chrm3tm1Mmt Chrm1tm1Kano/Chrm1tm1Kano,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88396  MGI:88398  MP:0005310 abnormal salivary gland physiology PMID: 15146045 
Chrm1tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MP:0001945 bronchoconstriction PMID: 14645675 
Chrm1tm1Kano|Chrm5tm1Minm Chrm1tm1Kano/Chrm1tm1Kano,Chrm5tm1Minm/Chrm5tm1Minm
involves: 129X1/SvJ * C57BL/6		 MGI:109248  MGI:88396  MP:0000505 decreased digestive secretion PMID: 15691866 
Chrm1tm1Stl Chrm1tm1Stl/Chrm1tm1Stl
involves: C57BL/6		 MGI:88396  MP:0002920 decreased paired-pulse facilitation PMID: 16290192 
Chrm1tm2.1Stl|Emx1tm1.1(cre)Ito Chrm1tm2.1Stl/Chrm1tm2.1Stl,Emx1tm1.1(cre)Ito/0
involves: 129P2/OlaHsd		 MGI:88396  MGI:95387  MP:0002920 decreased paired-pulse facilitation PMID: 20080609 
Chrm1tm2.1Stl|Tg(Grik4-cre)G32-4Stl Chrm1tm2.1Stl/Chrm1tm2.1Stl,Tg(Grik4-cre)G32-4Stl/0
involves: 129P2/OlaHsd * C57BL/6		 MGI:2448783  MGI:88396  MP:0002920 decreased paired-pulse facilitation PMID: 20080609 
Chrm1tm1Kano|Chrm3tm1Mmt Chrm1tm1Kano/Chrm1tm1Kano,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88396  MGI:88398  MP:0000623 decreased salivation PMID: 15146045 
Chrm1tm1Jwe|Chrm4tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MGI:88399  MP:0002917 decreased synaptic depression PMID: 15919709 
Chrm1tm1Jwe Chrm1tm1Jwe/Chrm1tm1Jwe
involves: 129S6/SvEvTac * CF-1		 MGI:88396  MP:0005079 defective cytotoxic T cell cytolysis PMID: 15913791 
Chrm1tm1Stl Chrm1tm1Stl/Chrm1tm1Stl
C57BL/6-Chrm1		 MGI:88396  MP:0001399 hyperactivity PMID: 11752469 
Chrm1+|Chrm1tm1Stl Chrm1tm1Stl/Chrm1+
C57BL/6-Chrm1		 MGI:88396  MP:0001399 hyperactivity PMID: 11752469 
Chrm1tm1Stl Chrm1tm1Stl/Chrm1tm1Stl
C57BL/6-Chrm1		 MGI:88396  MP:0001906 increased dopamine level PMID: 11752469 
Chrm1tm1Stl Chrm1tm1Stl/Chrm1tm1Stl
involves: C57BL/6		 MGI:88396  MP:0001475 reduced long term depression PMID: 16290192 
Biologically Significant Variants Click here for help
Type:  Single nucleotide polymorphism
Species:  Human
Description:  Cys417 is a highly conserved residue in TM7 and is essential to receptor function. A rare Cys417 -> Arg mutation has been found in the human genome with possible physiological consequences.
References:  85
General Comments
For reviews on muscarinic receptor knockout mice see [20,92,154-156].

References

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1. Abdul-Ridha A, Lane JR, Mistry SN, López L, Sexton PM, Scammells PJ, Christopoulos A, Canals M. (2014) Mechanistic insights into allosteric structure-function relationships at the M1 muscarinic acetylcholine receptor. J Biol Chem, 289 (48): 33701-11. [PMID:25326383]

2. Abdul-Ridha A, López L, Keov P, Thal DM, Mistry SN, Sexton PM, Lane JR, Canals M, Christopoulos A. (2014) Molecular determinants of allosteric modulation at the M1 muscarinic acetylcholine receptor. J Biol Chem, 289 (9): 6067-79. [PMID:24443568]

3. Akbulut H, Gören Z, Iskender E, Eraslan A, Ozdemir O, Oktay S. (1999) Subtypes of muscarinic receptors in rat duodenum: a comparison with rabbit vas deferens, rat atria, guinea-pig ileum and gallbladder by using imperialine. Gen Pharmacol, 32 (4): 505-11. [PMID:10323493]

4. Anagnostaras SG, Murphy GG, Hamilton SE, Mitchell SL, Rahnama NP, Nathanson NM, Silva AJ. (2003) Selective cognitive dysfunction in acetylcholine M1 muscarinic receptor mutant mice. Nat Neurosci, 6 (1): 51-8. [PMID:12483218]

5. Auerbach SS, DrugMatrix® and ToxFX® Coordinator National Toxicology Program. National Toxicology Program: Dept of Health and Human Services. Accessed on 02/05/2014. Modified on 02/05/2014. DrugMatrix, https://ntp.niehs.nih.gov/drugmatrix/index.html

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8. Beshore DC, N Di Marco C, Chang RK, Greshock TJ, Ma L, Wittmann M, Seager MA, Koeplinger KA, Thompson CD, Fuerst J et al.. (2018) MK-7622: A First-in-Class M1 Positive Allosteric Modulator Development Candidate. ACS Med Chem Lett, 9 (7): 652-656. [PMID:30034595]

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13. Boudinot E, Yamada M, Wess J, Champagnat J, Foutz AS. (2004) Ventilatory pattern and chemosensitivity in M1 and M3 muscarinic receptor knockout mice. Respir Physiol Neurobiol, 139 (3): 237-45. [PMID:15122990]

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16. Broad LM, Sanger HE, Mogg AJ, Colvin EM, Zwart R, Evans DA, Pasqui F, Sher E, Wishart GN, Barth VN et al.. (2019) Identification and pharmacological profile of SPP1, a potent, functionally selective and brain penetrant agonist at muscarinic M1 receptors. Br J Pharmacol, 176 (1): 110-126. [PMID:30276808]

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19. Burke RE. (1986) The relative selectivity of anticholinergic drugs for the M1 and M2 muscarinic receptor subtypes. Mov Disord, 1 (2): 135-44. [PMID:2904117]

20. Bymaster FP, McKinzie DL, Felder CC, Wess J. (2003) Use of M1-M5 muscarinic receptor knockout mice as novel tools to delineate the physiological roles of the muscarinic cholinergic system. Neurochem Res, 28 (3-4): 437-42. [PMID:12675128]

21. Böhme TM, Keim C, Kreutzmann K, Linder M, Dingermann T, Dannhardt G, Mutschler E, Lambrecht G. (2003) Structure-activity relationships of dimethindene derivatives as new M2-selective muscarinic receptor antagonists. J Med Chem, 46 (5): 856-67. [PMID:12593665]

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