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M2 receptor

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Target not currently curated in GtoImmuPdb

Target id: 14

Nomenclature: M2 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 7 466 7q33 CHRM2 cholinergic receptor muscarinic 2 3,10-11,104,160
Mouse 7 466 6 B1 Chrm2 cholinergic receptor, muscarinic 2, cardiac 82
Rat 7 466 4q22 Chrm2 cholinergic receptor, muscarinic 2 138
Previous and Unofficial Names Click here for help
M2 muscarinic acetylcholine receptor | AChR M2 | Chrm-2 | cholinergic receptor, muscarinic 2 | cholinergic receptor | cholinergic receptor, muscarinic 2, cardiac
Database Links Click here for help
Specialist databases
GPCRdb acm2_human (Hs), acm2_mouse (Mm), acm2_rat (Rn)
Other databases
Alphafold P08172 (Hs), Q9ERZ4 (Mm), P10980 (Rn)
ChEMBL Target CHEMBL211 (Hs), CHEMBL3197 (Mm), CHEMBL309 (Rn)
DrugBank Target P08172 (Hs)
Ensembl Gene ENSG00000181072 (Hs), ENSMUSG00000045613 (Mm), ENSRNOG00000046972 (Rn)
Entrez Gene 1129 (Hs), 243764 (Mm), 81645 (Rn)
Human Protein Atlas ENSG00000181072 (Hs)
KEGG Gene hsa:1129 (Hs), mmu:243764 (Mm), rno:81645 (Rn)
OMIM 118493 (Hs)
Pharos P08172 (Hs)
RefSeq Nucleotide NM_000739 (Hs), NM_203491 (Mm), NM_031016 (Rn)
RefSeq Protein NP_000730 (Hs), NP_987076 (Mm), NP_112278 (Rn)
SynPHARM 1190 (in complex with [3H]QNB)
UniProtKB P08172 (Hs), Q9ERZ4 (Mm), P10980 (Rn)
Wikipedia CHRM2 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist
PDB Id:  3UON
Ligand:  3-quinuclidinyl-benzilate
Resolution:  3.0Å
Species:  Human
References:  47
Image of receptor 3D structure from RCSB PDB
Description:  Structure of active human M2 muscarinic acetylcholine receptor bound to the agonist iperoxo
PDB Id:  4MQS
Ligand:  iperoxo
Resolution:  3.5Å
Species:  Human
References:  68
Image of receptor 3D structure from RCSB PDB
Description:  Structure of active human M2 muscarinic acetylcholine receptor bound to the agonist iperoxo and allosteric modulator LY2119620
PDB Id:  4MQT
Ligand:  LY2119620
Resolution:  3.7Å
Species:  Human
References:  68
Natural/Endogenous Ligands Click here for help
acetylcholine

Download all structure-activity data for this target as a CSV file go icon to follow link

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 10.1 pKd 114
⤷ pKd 10.1 (Kd 8x10-11 M) [114]
[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 8.8 pKd 74
⤷ pKd 8.8 [74]
[3H]oxotremorine-M Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist 8.7 pKd 6
⤷ pKd 8.7 [6]
NNC 11-1585 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 10.1 pKi 24
⤷ pKi 10.1 [24]
NNC 11-1607 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.2 pKi 24
⤷ pKi 8.2 [24]
pentylthio-TZTP Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.9 pKi 61
⤷ pKi 7.9 [61]
methacholine Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Rn Agonist 7.2 pKi 102,110
⤷ pKi 7.2 (Ki 5.9x10-8 M) [102,110]
NNC 11-1314 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.2 pKi 24
⤷ pKi 7.2 [24]
xanomeline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 6.9 – 7.4 pKi 105,147,154
⤷ pKi 6.9 – 7.4 [105,147,154]
oxotremorine Small molecule or natural product Click here for species-specific activity table Rn Full agonist 6.5 pKi 67
⤷ pKi 6.5 [67]
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 6.4 pKi 67
⤷ pKi 6.4 [67]
cevimeline Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 6.1 pKi 80
⤷ pKi 6.1 (Ki 8.54x10-7 M) [80]
Description: Displacement of [3H]QNB from cloned receptor.
oxotremorine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.0 – 6.6 pKi 61,110
⤷ pKi 5.0 – 6.6 [61,110]
arecaidine propargyl ester Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.7 pKi 61
⤷ pKi 5.7 [61]
carbachol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Full agonist 5.7 pKi 67
⤷ pKi 5.7 [67]
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 – 6.5 pKi 23,61,65
⤷ pKi 4.3 – 6.5 [23,61,65]
McN-A-343 Small molecule or natural product Click here for species-specific activity table Rn Partial agonist 4.7 – 6.0 pKi 71
⤷ pKi 4.7 – 6.0 [71]
arecoline Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.2 pKi 61,100,110
⤷ pKi 5.2 [61,100,110]
carbachol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 4.2 – 5.7 pKi 23,61
⤷ pKi 4.2 – 5.7 [23,61]
methylfurmethide Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.9 pKi 61
⤷ pKi 4.9 [61]
oxotremorine-M Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.9 pKi 61
⤷ pKi 4.9 [61]
pilocarpine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 4.9 pKi 61,110
⤷ pKi 4.9 [61,110]
furtrethonium Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.5 pKi 61
⤷ pKi 4.5 [61]
bethanechol Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Full agonist 4.0 pKi 61,110
⤷ pKi 4.0 [61,110]
iperoxo Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 9.8 pEC50 114-115
⤷ pEC50 9.8 [114-115]
(+)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 6.2 – 6.4 pEC50 35,46
⤷ pEC50 6.2 – 6.4 [35,46]
(-)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.6 – 5.7 pEC50 35,46
⤷ pEC50 5.6 – 5.7 [35,46]
[18F]FP-TZTP Small molecule or natural product Ligand is labelled Ligand is radioactive Mm Full agonist - - 59
⤷ [59]
View species-specific agonist tables
Agonist Comments
The binding data for McN-A-343 [71] is found on rat heart.
Please consult references [13,75,110,146,153] for further details of the activity of some of the ligands in this list.
Pilocarpine has been found to be a partial agonist [75,153] and a full agonist [146] at the M2 receptor.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Antagonist >6.3 pA2 99
⤷ pA2 >6.3 [99]
[3H]QNB Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 10.1 – 10.6 pKd 60,104
⤷ pKd 10.1 – 10.6 (Kd 7.94x10-11 – 2.51x10-11 M) [60,104]
[3H]tiotropium Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 10.3 pKd 112
⤷ pKd 10.3 [112]
[3H]N-methyl scopolamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.3 – 9.9 pKd 20,52,60,62,66,73,146
⤷ pKd 9.3 – 9.9 (Kd 5.2x10-10 – 1.4x10-10 M) [20,52,60,62,66,73,146]
[3H]clidinium Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Antagonist 9.6 pKd 67
⤷ pKd 9.6 [67]
[3H]N-methyl scopolamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Rn Antagonist 9.5 pKd 124
⤷ pKd 9.5 [124]
[3H]clidinium Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist 9.5 pKd 67
⤷ pKd 9.5 [67]
[3H]4NMPB Small molecule or natural product Ligand is labelled Ligand is radioactive Rn Antagonist 9.4 pKd 124
⤷ pKd 9.4 [124]
[3H]AF DX-384 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.0 pKd 21,89,142
⤷ pKd 9.0 [21,89,142]
biperiden Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.2 pKd 9
⤷ pKd 8.2 (Kd 6.3x10-9 M) [9]
Cy3B-telenzepine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Hs Antagonist 10.4 pKi 95
⤷ pKi 10.4 [95]
tiotropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.9 – 10.7 pKi 31,107,131,133
⤷ pKi 9.9 – 10.7 [31,107,131,133]
umeclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.8 pKi 70,112
⤷ pKi 9.8 (Ki 1.5x10-10 M) [70,112]
tripitramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.6 pKi 81
⤷ pKi 9.6 [81]
ipratropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.3 – 9.8 pKi 52,107
⤷ pKi 9.3 – 9.8 [52,107]
revefenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.5 pKi 51
⤷ pKi 9.5 (Ki 3.02x10-10 M) [51]
Description: Determined from a radioligand binding assay using membranes from CHO‐K1 cells expressing the hM2 receptor, and displacement of [3H]NMS tracer.
propantheline Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.5 pKi 54
⤷ pKi 9.5 [54]
THRX160209 Small molecule or natural product Hs Antagonist 9.5 pKi 125
⤷ pKi 9.5 [125]
mepenzolic acid Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.2 pKi 155
⤷ pKi 9.2 (Ki 6.8x10-10 M) [155]
atropine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 9.0 – 9.1 pKi 64,67
⤷ pKi 9.0 – 9.1 [64,67]
dexetimide Small molecule or natural product Approved drug Primary target of this compound Hs Antagonist 8.9 pKi 67
⤷ pKi 8.9 [67]
dexetimide Small molecule or natural product Approved drug Rn Antagonist 8.8 pKi 67
⤷ pKi 8.8 [67]
Alexa-488-telenzepine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Hs Antagonist 8.8 pKi 95
⤷ pKi 8.8 [95]
scopolamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.7 pKi 9,54
⤷ pKi 8.7 [9,54]
SCH 57790 Small molecule or natural product Hs Antagonist 8.6 pKi 69
⤷ pKi 8.6 [69]
AE9C90CB Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.6 pKi 121
⤷ pKi 8.6 [121]
benzatropine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Antagonist 8.6 pKi 96
⤷ pKi 8.6 (Ki 2.6x10-9 M) [96]
Description: Displacement binding assay using homogenised rat caudate putamen.
atropine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.8 – 9.2 pKi 28,52,54,104
⤷ pKi 7.8 – 9.2 [28,52,54,104]
tolterodine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inverse agonist 8.4 – 8.5 pKi 44,121
⤷ pKi 8.4 – 8.5 [44,121]
4-DAMP Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.4 pKi 33
⤷ pKi 8.4 [33]
AQ-RA 741 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.4 pKi 33,44
⤷ pKi 8.4 [33,44]
4-DAMP Small molecule or natural product Click here for species-specific activity table Rn Antagonist 8.2 pKi 64,67
⤷ pKi 8.2 [64,67]
himbacine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 – 8.4 pKi 33,63,67,88
⤷ pKi 7.9 – 8.4 [33,63,67,88]
AFDX384 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.1 – 8.2 pKi 28,33
⤷ pKi 8.1 – 8.2 [28,33]
ethopropazine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 8.1 pKi 15
⤷ pKi 8.1 (Ki 7.2x10-9 M) [15]
Description: Displacement of [H]QNB binding in rat hindbrain brain homogenate.
oxybutynin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.9 – 8.1 pKi 30,121
⤷ pKi 7.9 – 8.1 [30,121]
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 7.9 pKi 123
⤷ pKi 7.9 (Ki 1.18x10-8 M) [123]
oxybutynin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inverse agonist 7.9 pKi 30
⤷ pKi 7.9 (Ki 1.175x10-8 M) [30]
himbacine Small molecule or natural product Rn Antagonist 7.9 pKi 67
⤷ pKi 7.9 [67]
methoctramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.3 – 8.4 pKi 14,33,37,50,67,94
⤷ pKi 7.3 – 8.4 [14,33,37,50,67,94]
hexocyclium Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.6 pKi 14
⤷ pKi 7.6 [14]
(S)-dimetindene Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 7.5 pKi 18
⤷ pKi 7.5 (Ki 3.02x10-8 M) [18]
Description: Binding to hM2 receptors expressed in CHO cells.
silahexocyclium Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.5 pKi 14
⤷ pKi 7.5 [14]
UH-AH 37 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.3 – 7.4 pKi 44,152
⤷ pKi 7.3 – 7.4 [44,152]
methoctramine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.3 pKi 67
⤷ pKi 7.3 [67]
darifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inverse agonist 7.2 – 7.3 pKi 44,52,121
⤷ pKi 7.2 – 7.3 [44,52,121]
tropicamide Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.2 pKi 28
⤷ pKi 7.2 [28]
solifenacin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 6.9 – 7.1 pKi 55,121
⤷ pKi 6.9 – 7.1 [55,121]
dosulepin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.0 pKi 123
⤷ pKi 7.0 (Ki 1.09x10-7 M) [123]
otenzepad Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.7 – 7.2 pKi 14,67
⤷ pKi 6.7 – 7.2 [14,67]
imipramine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 6.9 pKi 67
⤷ pKi 6.9 [67]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.7 – 6.8 pKi 64,67
⤷ pKi 6.7 – 6.8 [64,67]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.6 – 6.8 pKi 14,37,67
⤷ pKi 6.6 – 6.8 [14,37,67]
hexahydrodifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.7 pKi 14
⤷ pKi 6.7 [14]
dicyclomine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.6 pKi 14
⤷ pKi 6.6 [14]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 5.3 – 7.4 pKi 64,67,124
⤷ pKi 5.3 – 7.4 [64,67,124]
p-F-HHSiD Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.1 – 6.6 pKi 37,54
⤷ pKi 6.1 – 6.6 [37,54]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.0 – 6.7 pKi 14,33,50,54,63,67,94,152
⤷ pKi 6.0 – 6.7 [14,33,50,54,63,67,94,152]
VU0255035 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.2 pKi 119
⤷ pKi 6.2 [119]
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Antagonist <6.0 pKi 63
⤷ pKi <6.0 [63]
otenzepad Small molecule or natural product Click here for species-specific activity table Rn Antagonist 4.6 – 7.3 pKi 64,67,124
⤷ pKi 4.6 – 7.3 [64,67,124]
lithocholylcholine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.4 pKi 23
⤷ pKi 5.4 [23]
guanylpirenzepine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 5.3 pKi 145
⤷ pKi 5.3 [145]
muscarinic toxin 7 Peptide Click here for species-specific activity table Hs Antagonist <5.0 pKi 97
⤷ pKi <5.0 [97]
levetimide Small molecule or natural product Hs Antagonist 5.0 pKi 67
⤷ pKi 5.0 [67]
levetimide Small molecule or natural product Rn Antagonist 4.8 pKi 67
⤷ pKi 4.8 [67]
ML381 Small molecule or natural product Click here for species-specific activity table Hs Antagonist <4.5 pKi 42
⤷ pKi <4.5 (Ki >3x10-5 M) [42]
aclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 10.1 pIC50 107,133
⤷ pIC50 10.1 [107,133]
glycopyrrolate Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 8.7 – 9.5 pIC50 128,131
⤷ pIC50 8.7 – 9.5 [128,131]
solifenacin Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 6.2 pIC50 106
⤷ pIC50 6.2 (IC50 5.73x10-7 M) [106]
View species-specific antagonist tables
Antagonist Comments
Dexetimide is the optical isomer of levetimide [67].

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 [9].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[3H]dimethyl-W84 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Positive 8.5 pKd 137
⤷ pKd 8.5 [137]
C7/3-phth Small molecule or natural product Hs Negative 7.1 pKd 2,25
⤷ pKd 7.1 [2,25]
W-84 Small molecule or natural product Hs Negative 6.0 – 7.5 pKd 91,137
⤷ pKd 6.0 – 7.5 [91,137]
alcuronium Small molecule or natural product Click here for species-specific activity table Hs Negative 6.1 – 6.9 pKd 2,61,137
⤷ pKd 6.1 – 6.9 [2,61,137]
gallamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Negative 5.9 – 6.3 pKd 26,73
⤷ pKd 5.9 – 6.3 [26,73]
WIN 51,708 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.9 pKd 78
⤷ pKd 5.9 [78]
KT 5823 Small molecule or natural product Click here for species-specific activity table Hs Positive 5.7 pKd 77
⤷ pKd 5.7 [77]
LY2119620 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 5.5 – 5.7 pKd 29,68
⤷ pKd 5.5 – 5.7 [29,68]
WIN 62,577 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.3 pKd 78
⤷ pKd 5.3 [78]
staurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 5.1 pKd 77
⤷ pKd 5.1 [77]
vincamine Small molecule or natural product Click here for species-specific activity table Hs Neutral 5.1 pKd 61
⤷ pKd 5.1 [61]
Gö 7874 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.0 pKd 77
⤷ pKd 5.0 [77]
strychnine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 4.9 – 5.0 pKd 61,73,137
⤷ pKd 4.9 – 5.0 [61,73,137]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.8 pKd 76
⤷ pKd 4.8 [76]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.8 pKd 76
⤷ pKd 4.8 [76]
N-chloromethyl-brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.6 pKd 76
⤷ pKd 4.6 [76]
N-chloromethyl-brucine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.6 pKd 76
⤷ pKd 4.6 [76]
brucine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.3 – 4.6 pKd 61,76
⤷ pKd 4.3 – 4.6 [61,76]
LY2033298 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 4.4 pKd 141
⤷ pKd 4.4 [141]
brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.3 pKd 76
⤷ pKd 4.3 [76]
vinburnine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.2 pKd 61
⤷ pKd 4.2 [61]
thiochrome Small molecule or natural product Click here for species-specific activity table Hs Neutral 3.9 pKd 74
⤷ pKd 3.9 [74]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Negative 3.5 pKd 76
⤷ pKd 3.5 [76]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Positive 3.5 pKd 76
⤷ pKd 3.5 [76]
dimethyl-W84 Small molecule or natural product Hs Positive 8.5 pKi 137
⤷ pKi 8.5 [137]
W-84 Small molecule or natural product Hs Positive 7.6 pKi 137
⤷ pKi 7.6 [137]
WDuo3 Small molecule or natural product Hs Positive 6.9 pKi 137
⤷ pKi 6.9 [137]
gallamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Negative 5.8 – 7.6 pKi 67,92,137
⤷ pKi 5.8 – 7.6 [67,92,137]
gallamine Small molecule or natural product Approved drug Ligand has a PDB structure Rn Negative 5.6 pKi 67
⤷ pKi 5.6 [67]
Duo3 Small molecule or natural product Hs Positive 7.1 pEC50 136
⤷ pEC50 7.1 [136]
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 122
⤷ pIC50 5.7 (IC50 2.1x10-6 M) [122]
View species-specific allosteric modulator tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
References:  87,103
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gs family
Gq/G11 family 		Adenylyl cyclase stimulation
Phospholipase C stimulation
References:  46,86
Tissue Distribution Click here for help
Ciliary muscle.
Species:  Human
Technique:  In situ hybridisation and Northern blotting.
References:  159
CNS: cerebral cortex, thalamus, brainstem, medulla, hypothalamus.
Species:  Human
Technique:  Radioligand binding.
References:  27
Vestibular system.
Species:  Human
Technique:  RT-PCR.
References:  144
Esophageal smooth muscle.
Species:  Human
Technique:  Radioligand binding.
References:  108
Bladder.
Species:  Human
Technique:  RT-PCR.
References:  139
CNS: forebrain.
Species:  Mouse
Technique:  immunocytochemistry.
References:  53
CNS: cerebral cortex, corpus striatum, hippocampus, thalamus, hypothalamus, midbrain, pons-medulla, cerebellum, spinal cord.
Species:  Mouse
Technique:  Radioligand binding.
References:  98
Intestinal smooth muscle.
Species:  Rat
Technique:  Radioligand binding.
References:  19
CNS: pons.
Species:  Rat
Technique:  Radioligand binding.
References:  4
CNS: hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  79
CNS: caudate putamen.
Species:  Rat
Technique:  in situ hybridisation.
References:  148
Heart: intrinsic neurons.
Species:  Rat
Technique:  in situ hybridisation.
References:  49
Salivary gland: submandibular ganglion.
Species:  Rat
Technique:  Immunohistochemistry.
References:  120
Vestibular system.
Species:  Rat
Technique:  RT-PCR.
References:  144
CNS: basal forebrain, parabigeminal nucleus, pedunculopontine and laterodorsal tegmental nuclei, cranial nerve nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  143
CNS: cerebral cortex, hipocampus, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum.
Species:  Rat
Technique:  Immunoprecipitation.
References:  156
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 cAMP levels in CHO cells transfected with the human M2 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  20,23-24,110
Measurement of cAMP levels in mouse Y1 adrenal cells transfected with the mouse M2 receptor.
Species:  Mouse
Tissue:  Y1 adrenal cells.
Response measured:  Inhibition of cAMP accumulation.
References:  118
Measurement of cAMP levels in JEG-3 cells transfected with the human M2 receptor, using a cAMP response element (CRE)-coupled luciferase construct as the reporter.
Species:  Human
Tissue:  JEG-3 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  87
Measurement of cAMP levels in dissociated rat cortical tissue endogenously expressing the M2 receptor.
Species:  Rat
Tissue:  Cortical tissue.
Response measured:  Inhibition of cAMP accumulation.
References:  1
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:  111
Measurement of GIRK channel activity in Xenopus oocytes transfected with the human M2 receptor.
Species:  Human
Tissue:  Xenopus oocytes.
Response measured:  Activation of GIRK channels.
References:  157
Measurement of GIRK channel activity in rat superior cervical ganglion neurons endogenously expressing the M2 receptor.
Species:  Rat
Tissue:  Superior cervical ganglion neurons.
Response measured:  Activation of GIRK channels.
References:  39-40
Measurement of AC activity in rat myocardial homogenates endogenously expressing the M2 receptor.
Species:  Rat
Tissue:  Myocardial homogenates.
Response measured:  Inhibition of AC activity.
References:  36
Measurement of the effects of a ligand on the level, or rate, of binding of GTPγ35S to membranes.
Species:  Human
Tissue:  CHO cells.
Response measured:  The binding of GTPγ35S to G proteins coupled to the receptor.
References:  7,72-75,77-78
Measurement of the effects of a ligand on the rate of hydrolysis of GTP by G proteins in membranes.
Species:  Human
Tissue:  CHO cell membranes.
Response measured:  Generation of 32Pi from [γ-32P]GTP.
References:  75
Physiological Functions Click here for help
Vasodilation.
Species:  Rat
Tissue:  Pulmonary artery.
References:  85
Mediation of colonic motor responses to eating.
Species:  Human
Tissue:  In vivo.
References:  93
Hypertension.
Species:  Rat
Tissue:  In vivo.
References:  101
Stimulation of pancreatic secretion.
Species:  Rat
Tissue:  In vivo.
References:  22
Stimulation of water consumption.
Species:  Rat
Tissue:  In vivo.
References:  48
Control of small intestinal motility.
Species:  Rat
Tissue:  In vivo.
References:  38
Hypotension.
Species:  Rat
Tissue:  In vivo.
References:  130
Bradycardia.
Species:  Rat
Tissue:  In vivo.
References:  130
Thermal automodulator.
Species:  Rat
Tissue:  In vivo.
References:  117
Autoreceptor: modulation of ACh release.
Species:  Human
Tissue:  Bronchi.
References:  90,134
Stimulation of histamine release.
Species:  Rat
Tissue:  Stomach.
References:  113
Spinal analgesia.
Species:  Rat
Tissue:  In vivo.
References:  43
Autoreceptor: modulation of ACh release.
Species:  Rat
Tissue:  Heart.
References:  8
Locomotor activity.
Species:  Rat
Tissue:  In vivo.
References:  12
Modulation of the sleep-wake cycle.
Species:  Rat
Tissue:  In vivo.
References:  56-58
Physiological Consequences of Altering Gene Expression Click here for help
Atrial preparations from M2 receptor knockout mice do not exhibit agonist-induced bradycardia as seen in wild-type atrial preparations.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  16,45,127
M2 receptor knockout mice do not exhibit agonist-induced tremor as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  45
M2 receptor knockout mice exhibit reduced agonist-induced hypothermia as compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  45
M2 receptor knockout mice exhibit reduced agonist-induced antinociception compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  32,45
Smooth muscle preparations (stomach fundus, urinary bladder, trachea, gallbladder) from M2 receptor knockout mice exhibit reduced agonist-induced contractions compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  16,126-127
Hippocampal, cortical and striatal brain slices from M2/M4 double knockout mice lack muscarinic agonist-induced inhibition of acetylcholine release that is seen with wild-type brain slices.
From M2 receptor single knockout mice, the hippocampal and cortical slices exhibit this loss of inhibition of acetylcholine release, but the inhibition remains in the striatal slices.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  158
Skin preparations from M2 receptor knockout mice no longer show muscarinic-induced desensitisation of peripheral nociception.
In addition, the heat-induced release of CGRP which is inhibited by muscarine in wild-type mice is unaltered in M2 knockout mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  5
Tissue from atria, bladder and vas deferens of M2 receptor knockout mice exhibit reduced agonist-induced inhibition of noradrenaline release compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  135
Smooth muscle preparations (ileum, trachea, urinary bladder) from M2 receptor knockout mice exhibit increased relaxant effects of forskolin and isoproterenol against agonist-induced contractions.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  34,83
M2 receptor knockout mice exhibit a reduced muscarinic antagonist-induced increase in hippocampal acetylcholine release compared to wild-type mice.
M2/M4 double knockout mice completely lack this response.
In addition, M2 and M2/M4 knockout mice exhibit an increase in hippocampal acetylcholine release in response to a novel environment.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  140
Lung slices from M2 receptor knockout mice exhibit reduced agonist-induced bronchoconstriction compared to wild-type mice.
This bronchoconstriction is completely abolished in M2/M3 double knockout mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  129
M2 receptor knockout mice do not exhibit agonist-induced or vagally-stimulated bradycardia in vivo as seen in wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  41
M2 receptor knockout mice exhibit increased agonist-induced or vagally-stimulated bronchoconstriction in vivo compared to wild-type mice.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  41
M2 receptor knockout mice exhibit impaired behavioural flexibility, working memory and hippocampal plasticity.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  116
M2 receptor knockout mice exhibit increased agonist/stress-induced pituitary-adrenal responses.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  109
Smooth muscle from the small intestine of M2 receptor knockout mice do not exhibit any alteration in EFS-induced acetylcholine release.
However, M2/M4 double knockout mice exhibit an increase in acetylcholine release.
Overall, it is thought that both M2 and M4 receptors mediate the autoinhibitory control of acetylcholine release in the mouse ileum, and that each can compensate for loss of the other.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  132
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
Chrm2tm1Jwe|Chrm4tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S4/SvJae * 129S6/SvEvTac * CF-1		 MGI:88397  MGI:88399  MP:0004994 abnormal brain wave pattern PMID: 16110248 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0002206 abnormal CNS synaptic transmission PMID: 15919709 
Chrm2tm1Jwe|Chrm4tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe,Chrm4tm1Jwe/Chrm4tm1Jwe
involves: 129S4/SvJae * 129S6/SvEvTac * CF-1		 MGI:88397  MGI:88399  MP:0002206 abnormal CNS synaptic transmission PMID: 15919709 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0005085 abnormal gallbladder physiology PMID: 11961069 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0001629 abnormal heart rate PMID: 10688600 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
B6.129S4-Chrm2		 MGI:88397  MP:0002566 abnormal sexual interaction PMID: 18382674 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
B6.129S4-Chrm2		 MGI:88397  MP:0001529 abnormal vocalization PMID: 18382674 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0001945 bronchoconstriction PMID: 14645675 
Chrm2tm1Jwe|Chrm3tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe,Chrm3tm1Jwe/Chrm3tm1Jwe
involves: 129S4/SvJae * 129S6/SvEvTac * CF-1		 MGI:88397  MGI:88398  MP:0001945 bronchoconstriction PMID: 14645675 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0001262 decreased body weight PMID: 9990086 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0001982 decreased chemically-elicited antinociception PMID: 9990086 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 9990086 
Chrm2+|Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2+
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0008874 decreased physiological sensitivity to xenobiotic PMID: 9990086 
Chrm2tm1Minm|Chrm3tm1Mmt Chrm2tm1Minm/Chrm2tm1Minm,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88397  MGI:88398  MP:0000539 distended urinary bladder PMID: 12486155 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0009747 impaired behavioral response to xenobiotic PMID: 10688600 
Chrm2+|Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2+
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0009747 impaired behavioral response to xenobiotic PMID: 9990086 
Chrm2tm1Minm|Chrm3tm1Mmt Chrm2tm1Minm/Chrm2tm1Minm,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88397  MGI:88398  MP:0000742 impaired contractility of ileal smooth muscle PMID: 12486155 
Chrm2tm1Jwe Chrm2tm1Jwe/Chrm2tm1Jwe
involves: 129S4/SvJae * CF-1		 MGI:88397  MP:0000740 impaired smooth muscle contractility PMID: 10688600  11961069 
Chrm2tm1Minm|Chrm3tm1Mmt Chrm2tm1Minm/Chrm2tm1Minm,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88397  MGI:88398  MP:0000740 impaired smooth muscle contractility PMID: 12486155 
Chrm2tm1Minm|Chrm3tm1Mmt Chrm2tm1Minm/Chrm2tm1Minm,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88397  MGI:88398  MP:0002546 mydriasis PMID: 12486155 
Chrm2tm1Minm|Chrm3tm1Mmt Chrm2tm1Minm/Chrm2tm1Minm,Chrm3tm1Mmt/Chrm3tm1Mmt
involves: 129X1/SvJ * C57BL/6		 MGI:88397  MGI:88398  MP:0001732 postnatal growth retardation PMID: 12486155 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Alcohol dependence
Disease Ontology: DOID:0050741
OMIM: 103780
General Comments
For reviews on muscarinic receptor knockout mice see [17,84,149-151].

References

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2. Avlani VA, Gregory KJ, Morton CJ, Parker MW, Sexton PM, Christopoulos A. (2007) Critical role for the second extracellular loop in the binding of both orthosteric and allosteric G protein-coupled receptor ligands. J Biol Chem, 282 (35): 25677-86. [PMID:17591774]

3. Badner JA, Yoon SW, Turner G, Bonner TI, Detera-Wadleigh SD. (1995) Multipoint genetic linkage analysis of the m2 human muscarinic receptor gene. Mamm Genome, 6 (7): 489-90. [PMID:7579899]

4. Baghdoyan HA. (1997) Location and quantification of muscarinic receptor subtypes in rat pons: implications for REM sleep generation. Am J Physiol, 273 (3 Pt 2): R896-904. [PMID:9321865]

5. Bernardini N, Roza C, Sauer SK, Gomeza J, Wess J, Reeh PW. (2002) Muscarinic M2 receptors on peripheral nerve endings: a molecular target of antinociception. J Neurosci, 22 (12): RC229. [PMID:12045234]

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13. Bräuner-Osborne H, Ebert B, Brann MR, Falch E, Krogsgaard-Larsen P. (1996) Functional partial agonism at cloned human muscarinic acetylcholine receptors. Eur J Pharmacol, 313 (1-2): 145-50. [PMID:8905341]

14. Buckley NJ, Bonner TI, Buckley CM, Brann MR. (1989) Antagonist binding properties of five cloned muscarinic receptors expressed in CHO-K1 cells. Mol Pharmacol, 35 (4): 469-76. [PMID:2704370]

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17. 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]

18. 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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21. Ch'ng SS, Walker AJ, McCarthy M, Le TK, Thomas N, Gibbons A, Udawela M, Kusljic S, Dean B, Gogos A. (2020) The Impact of Removal of Ovarian Hormones on Cholinergic Muscarinic Receptors: Examining Prepulse Inhibition and Receptor Binding. Brain Sci, 10 (2). [PMID:32079174]

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28. Croy CH, Chan WY, Castetter AM, Watt ML, Quets AT, Felder CC. (2016) Characterization of PCS1055, a novel muscarinic M4 receptor antagonist. Eur J Pharmacol, 782: 70-6. [PMID:27085897]

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41. Fisher JT, Vincent SG, Gomeza J, Yamada M, Wess J. (2004) Loss of vagally mediated bradycardia and bronchoconstriction in mice lacking M2 or M3 muscarinic acetylcholine receptors. FASEB J, 18 (6): 711-3. [PMID:14977875]

42. Gentry PR, Kokubo M, Bridges TM, Cho HP, Smith E, Chase P, Hodder PS, Utley TJ, Rajapakse A, Byers F et al.. (2014) Discovery, synthesis and characterization of a highly muscarinic acetylcholine receptor (mAChR)-selective M5-orthosteric antagonist, VU0488130 (ML381): a novel molecular probe. ChemMedChem, 9 (8): 1677-82. [PMID:24692176]

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