Top ▲

M4 receptor

Click here for help

Target not currently curated in GtoImmuPdb

Target id: 16

Nomenclature: M4 receptor

Family: Acetylcholine receptors (muscarinic)

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 7 479 11p11.2 CHRM4 cholinergic receptor muscarinic 4 3,35
Mouse 7 479 2 50.63 cM Chrm4 cholinergic receptor, muscarinic 4 59
Rat 7 478 3q24 Chrm4 cholinergic receptor, muscarinic 4 46,94,108
Previous and Unofficial Names Click here for help
HM3 [75-76] | Chrm-4 | cholinergic receptor, muscarinic 4 | cholinergic receptor
Database Links Click here for help
Specialist databases
GPCRdb acm4_human (Hs), acm4_mouse (Mm)
Other databases
Alphafold
ChEMBL Target
DrugBank Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the M4 muscarinic acetylcholine receptor (M4-mT4L) bound to tiotropium.
PDB Id:  5DSG
Ligand:  tiotropium
Resolution:  2.6Å
Species:  Human
References:  92
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 82
pKd 10.1 (Kd 8x10-11 M) [82]
[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 8.2 pKd 52
pKd 8.2 (Kd 6.3x10-9 M) [52]
pentylthio-TZTP Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.7 pKi 44
pKi 8.7 [44]
NNC 11-1585 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.6 pKi 17
pKi 8.6 [17]
NNC 11-1607 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 8.1 pKi 17
pKi 8.1 [17]
xanomeline Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 7.4 – 7.7 pKi 61,77,102,109
pKi 7.4 – 7.7 [61,77,102,109]
NNC 11-1314 Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.3 pKi 17
pKi 7.3 [17]
sabcomeline Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.2 pKi 109
pKi 7.2 [109]
McN-A-343 Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.6 – 6.7 pKi 49
pKi 5.6 – 6.7 [49]
cevimeline Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 6.0 pKi 58
pKi 6.0 (Ki 1.012x10-6 M) [58]
Description: Displacement of [3H]QNB from cloned receptor.
arecaidine propargyl ester Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.9 pKi 44
pKi 5.9 [44]
methacholine Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Rn Agonist 5.8 pKi 74,79
pKi 5.8 (Ki 1.6x10-6 M) [74,79]
arecoline Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.5 pKi 44,73,79
pKi 5.5 [44,73,79]
milameline Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 5.5 pKi 109
pKi 5.5 [109]
oxotremorine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.2 pKi 44,79
pKi 5.2 [44,79]
oxotremorine-M Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.2 pKi 44
pKi 5.2 [44]
pilocarpine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 5.2 pKi 44,79
pKi 5.2 [44,79]
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 4.5 – 5.6 pKi 44,47
pKi 4.5 – 5.6 [44,47]
methylfurmethide Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.7 pKi 44
pKi 4.7 [44]
carbachol Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Full agonist 4.3 – 4.9 pKi 44,109
pKi 4.3 – 4.9 [44,109]
furtrethonium Small molecule or natural product Click here for species-specific activity table Hs Full agonist 4.3 pKi 44
pKi 4.3 [44]
bethanechol Small molecule or natural product Approved drug Click here for species-specific activity table Hs Full agonist 4.0 pKi 44,79
pKi 4.0 [44,79]
(+)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 5.4 pEC50 27
pEC50 5.4 [27]
(-)-aceclidine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 4.8 pEC50 27
pEC50 4.8 [27]
iperoxo Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Agonist - - 82
[82]
View species-specific agonist tables
Agonist Comments
The binding data for McN-A-343 [49] is found on rat striatum.
Please consult references [5,53,79,101] for further details of the activity of some of the ligands in this list.
McN-A-343 and pilocarpine have been found to be partial agonists [53] and full agonists [79,101] at the M4 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 9.7 – 10.5 pKd 43,75
pKd 9.7 – 10.5 (Kd 2x10-10 – 3.16x10-11 M) [43,75]
[3H]N-methyl scopolamine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.9 – 10.2 pKd 11,43-44,48,51,101
pKd 9.9 – 10.2 (Kd 1.4x10-10 – 6x10-11 M) [11,43-44,48,51,101]
[3H]AF DX-384 Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 8.7 pKd 12,64,97
pKd 8.7 [12,64,97]
biperiden Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.6 pKd 2
pKd 8.6 (Kd 2.4x10-9 M) [2]
otenzepad Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.0 pKd 28
pKd 7.0 [28]
tiotropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 10.2 – 10.6 pKi 89,91
pKi 10.2 – 10.6 [89,91]
3-quinuclidinyl-benzilate Small molecule or natural product Hs Antagonist 10.4 pKi 10
pKi 10.4 (Ki 4x10-11 M) [10]
umeclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 10.3 pKi 81
pKi 10.3 [81]
propantheline Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 10.2 pKi 42
pKi 10.2 [42]
aclidinium Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 10.0 pKi 91
pKi 10.0 [91]
oxyphenonium Small molecule or natural product Approved drug Hs Antagonist 9.8 pKi 10
pKi 9.8 (Ki 1.45x10-10 M) [10]
atropine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 9.7 pKi 46
pKi 9.7 [46]
glycopyrrolate Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.1 – 10.0 pKi 87,89
pKi 9.1 – 10.0 [87,89]
AE9C90CB Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.5 pKi 84
pKi 9.5 [84]
mepenzolic acid Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.4 pKi 10
pKi 9.4 (Ki 3.6x10-10 M) [10]
scopolamine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 9.1 – 9.5 pKi 2,42
pKi 9.1 – 9.5 [2,42]
revefenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.3 pKi 39
pKi 9.3 (Ki 5.5x10-10 M) [39]
Description: Determined from a radioligand binding assay using membranes from CHO‐K1 cells expressing the hM4 receptor, and displacement of [3H]NMS tracer.
ipratropium Small molecule or natural product Approved drug Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 9.2 pKi 40
pKi 9.2 [40]
4-DAMP Small molecule or natural product Click here for species-specific activity table Rn Antagonist 9.1 pKi 46
pKi 9.1 [46]
atropine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.7 – 9.5 pKi 19,40,42,76
pKi 8.7 – 9.5 [19,40,42,76]
4-DAMP Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.9 pKi 25
pKi 8.9 [25]
oxybutynin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.4 – 8.7 pKi 24,84
pKi 8.4 – 8.7 [24,84]
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Antagonist 8.5 pKi 10
pKi 8.5 (Ki 3x10-9 M) [10]
silahexocyclium Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.5 pKi 7
pKi 8.5 [7]
tolterodine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.3 – 8.4 pKi 32,84
pKi 8.3 – 8.4 [32,84]
UH-AH 37 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 – 8.4 pKi 32,107
pKi 8.3 – 8.4 [32,107]
hexocyclium Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 pKi 7
pKi 8.3 [7]
dicyclomine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.3 pKi 10
pKi 8.3 (Ki 5x10-9 M) [10]
PCS1055 Small molecule or natural product Hs Antagonist 8.2 pKi 19
pKi 8.2 [19]
himbacine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 – 8.4 pKi 10,25,45,63
pKi 8.4 (Ki 4x10-9 M) [10]
pKi 7.9 – 8.2 [25,45,63]
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 8.1 pKi 85
pKi 8.1 (Ki 7.2x10-9 M) [85]
AQ-RA 741 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.8 – 8.2 pKi 25,32
pKi 7.8 – 8.2 [25,32]
tripitramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.9 pKi 65
pKi 7.9 [65]
darifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.3 – 8.1 pKi 32,40,84
pKi 7.3 – 8.1 [32,40,84]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Rn Antagonist 7.7 pKi 46
pKi 7.7 [46]
AFDX384 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.3 – 8.0 pKi 19,25
pKi 7.3 – 8.0 [19,25]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.0 – 8.1 pKi 10,25,38,42,45,107
pKi 8.1 (Ki 8x10-9 M) [10]
pKi 7.0 – 7.6 [25,38,42,45,107]
PD 102807 Small molecule or natural product Hs Antagonist 7.4 – 7.6 pKi 19,70
pKi 7.4 – 7.6 [19,70]
p-F-HHSiD Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.1 – 7.5 pKi 28,42
pKi 7.1 – 7.5 [28,42]
dosulepin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 7.2 pKi 85
pKi 7.2 (Ki 6.1x10-8 M) [85]
hexahydrosiladifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.5 – 7.7 pKi 7,28
pKi 6.5 – 7.7 [7,28]
muscarinic toxin 1 Peptide Click here for species-specific activity table Hs Antagonist 7.1 pKi 36
pKi 7.1 [36]
hexahydrodifenidol Small molecule or natural product Click here for species-specific activity table Hs Antagonist 7.1 pKi 7
pKi 7.1 [7]
pirenzepine Small molecule or natural product Approved drug Click here for species-specific activity table Rn Antagonist 7.1 pKi 46
pKi 7.1 [46]
methoctramine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 6.6 – 7.5 pKi 7,25,28,38
pKi 6.6 – 7.5 [7,25,28,38]
tropicamide Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.9 pKi 10
pKi 6.9 [10]
solifenacin Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 6.8 pKi 84
pKi 6.8 [84]
(S)-dimetindene Small molecule or natural product Click here for species-specific activity table Immunopharmacology Ligand Hs Antagonist 6.5 pKi 9
pKi 6.5 (Ki 2.951x10-7 M) [9]
Description: Binding to hM4 receptors expressed in CHO cells.
otenzepad Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.5 pKi 46
pKi 6.5 [46]
guanylpirenzepine Small molecule or natural product Click here for species-specific activity table Rn Antagonist 6.2 pKi 100
pKi 6.2 [100]
muscarinic toxin 2 Peptide Click here for species-specific activity table Hs Antagonist 5.9 pKi 36
pKi 5.9 [36]
VU0255035 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.9 pKi 83
pKi 5.9 [83]
lithocholylcholine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 5.3 pKi 14
pKi 5.3 [14]
muscarinic toxin 7 Peptide Click here for species-specific activity table Hs Antagonist <5.0 pKi 66
pKi <5.0 [66]
ML381 Small molecule or natural product Click here for species-specific activity table Hs Antagonist >4.5 pKi 31
pKi >4.5 (Ki <3x10-5 M) [31]
View species-specific antagonist tables
Antagonist Comments
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 [2].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LY2033298 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 4.9 – 5.5 pKB 13,88
pKB 4.9 – 5.5 [13,88]
KT 5720 Small molecule or natural product Click here for species-specific activity table Hs Neutral 6.4 pKd 55
pKd 6.4 [55]
WIN 51,708 Small molecule or natural product Click here for species-specific activity table Hs Negative 6.2 pKd 56
pKd 6.2 [56]
WIN 62,577 Small molecule or natural product Click here for species-specific activity table Hs Negative 5.9 pKd 56
pKd 5.9 [56]
Gö 7874 Small molecule or natural product Click here for species-specific activity table Hs Neutral 5.7 pKd 55
pKd 5.7 [55]
alcuronium Small molecule or natural product Click here for species-specific activity table Hs Negative 5.6 pKd 44
pKd 5.6 [44]
LY2119620 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 5.5 pKd 20
pKd 5.5 [20]
brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.7 – 6.0 pKd 44,54
pKd 4.7 – 6.0 [44,54]
staurosporine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Neutral 5.3 pKd 55
pKd 5.3 [55]
strychnine Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Positive 4.8 – 5.0 pKd 44,51
pKd 4.8 – 5.0 [44,51]
vinburnine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.6 pKd 44
pKd 4.6 [44]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Negative 4.5 pKd 54
pKd 4.5 [54]
N-benzyl brucine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.5 pKd 54
pKd 4.5 [54]
N-chloromethyl-brucine Small molecule or natural product Click here for species-specific activity table Hs Neutral 4.4 pKd 54
pKd 4.4 [54]
vincamine Small molecule or natural product Click here for species-specific activity table Hs Positive 4.2 pKd 44
pKd 4.2 [44]
thiochrome Small molecule or natural product Click here for species-specific activity table Hs Positive 4.0 pKd 52
pKd 4.0 [52]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Neutral 3.6 pKd 54
pKd 3.6 [54]
brucine N-oxide Small molecule or natural product Click here for species-specific activity table Hs Positive 3.6 pKd 54
pKd 3.6 [54]
muscarinic toxin 3 Peptide Click here for species-specific activity table Hs Negative 8.7 pKi 45,69
pKi 8.7 [45,69]
VU0467154 Small molecule or natural product Ligand has a PDB structure Rn Positive 7.8 pEC50 6
pEC50 7.8 (EC50 1.78x10-8 M) [6]
VU0152100 Small molecule or natural product Rn Positive 6.4 pEC50 4
pEC50 6.4 (EC50 3.8x10-7 M) [4]
VU0152099 Small molecule or natural product Rn Positive 6.4 pEC50 4
pEC50 6.4 (EC50 4.03x10-7 M) [4]
VU0467154 Small molecule or natural product Ligand has a PDB structure Hs Positive 6.2 pEC50 6
pEC50 6.2 (EC50 6.31x10-7 M) [6]
Description: Potentiation of ACh response at human receptor
VU0467154 Small molecule or natural product Ligand has a PDB structure Monkey Positive 6.0 pEC50 6
pEC50 6.0 (EC50 1x10-6 M) [6]
VU0010010 Small molecule or natural product Hs Positive - - 18
[18]
View species-specific allosteric modulator tables
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
References:  62,75
Tissue Distribution Click here for help
Esophageal smooth muscle.
Species:  Human
Technique:  Radioligand binding.
References:  78
Bladder.
Species:  Human
Technique:  RT-PCR.
References:  95
CNS: forebrain.
Species:  Mouse
Technique:  immunocytochemistry.
References:  41
CNS: cerebral cortex, corpus striatum, thalamus, hypothalamus, pons-medulla.
Species:  Mouse
Technique:  Radioligand binding.
References:  67
Heart: intrinsic neurons.
Species:  Rat
Technique:  in situ hybridisation.
References:  37
CNS: basal forebrain, pedunculopontine and laterodorsal tegmental nuclei.
Species:  Rat
Technique:  in situ hybridisation.
References:  98
CNS: cerebral cortex, hippocampus, corpus striatum, olfactory tubercle, midbrain, pons-medulla, cerebellum.
Species:  Rat
Technique:  Immunoprecipitation.
References:  110
CNS: caudate putamen, nucleus accumbens, olfactory tubercle.
Species:  Rat
Technique:  in situ hybridisation.
References:  103
CNS: hippocampus.
Species:  Rat
Technique:  immunocytochemistry.
References:  57
Vestibular system.
Species:  Rat
Technique:  RT-PCR.
References:  99
Expression Datasets Click here for help

Show »

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]

There should be a chart of expression data here, you may need to enable JavaScript!
Functional Assays Click here for help
Measurement of IP1 levels in murine fibroblast cells (B82) transfected with the rat M4 receptor.
Species:  Rat
Tissue:  B82 cells.
Response measured:  Stimulation of IP1 accumulation.
References:  46
Measurement of cAMP levels in murine fibroblast cells (B82) transfected with the rat M4 receptor.
Species:  Rat
Tissue:  B82 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  46
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:  62
Measurement of cAMP levels in CHO cells transfected with the human M4 receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  17
Measurement of ERK1/2 activity in COS-7 cells transfected with the human M4 receptor.
Species:  Human
Tissue:  COS-7 cells.
Response measured:  Increase in ERK1/2 activity.
References:  80
Measurement of Ca2+ channel activity in rat superior cervical ganglion neurons endogenously expressing the M4 receptor.
Species:  Rat
Tissue:  Superior cervical ganglion neurons.
Response measured:  Inhibition of Ca2+ channels.
References:  29-30
Measurement of AC activity in rat striatal homogenates endogenously expressing the M4 receptor.
Species:  Rat
Tissue:  Corpus striatum.
Response measured:  Inhibition of AC activity.
References:  26,68
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:  1,50-53,55-56
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:  1,53
Physiological Functions