CHRM4

Summary

CHRM4 (cholinergic receptor muscarinic 4, HGNC:1953) is a protein-coding gene on chromosome 11p11.2, encoding Muscarinic acetylcholine receptor M4 (P08173). The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins.

The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The clinical implications of this receptor are unknown; however, mouse studies link its function to adenylyl cyclase inhibition.

Source: NCBI Gene 1132 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 54 total — 1 pathogenic, 1 likely-pathogenic
• Druggable target: yes — 106 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000741

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1953
Approved symbol	CHRM4
Name	cholinergic receptor muscarinic 4
Location	11p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000180720
Ensembl biotype	protein_coding
OMIM	118495
Entrez	1132

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000433765, ENST00000682254, ENST00000855139

RefSeq mRNA: 2 — MANE Select: NM_000741 NM_000741, NM_001366692

CCDS: CCDS44581

Canonical transcript exons

ENST00000682254 — 2 exons

Exon	Start	End
ENSE00003919819	46383789	46386586
ENSE00003920497	46391531	46391776

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 79.04.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0003 / max 78.1414, expressed in 220 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119516	1.0003	220

Top tissues by expression

262 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.04	silver quality
caudate nucleus	UBERON:0001873	76.95	gold quality
putamen	UBERON:0001874	76.48	gold quality
nucleus accumbens	UBERON:0001882	75.86	gold quality
right frontal lobe	UBERON:0002810	73.48	gold quality
spleen	UBERON:0002106	71.60	gold quality
prefrontal cortex	UBERON:0000451	71.38	gold quality
anterior cingulate cortex	UBERON:0009835	69.40	gold quality
cingulate cortex	UBERON:0003027	69.32	gold quality
small intestine Peyer’s patch	UBERON:0003454	69.27	gold quality
Brodmann (1909) area 9	UBERON:0013540	68.95	gold quality
left testis	UBERON:0004533	67.02	gold quality
frontal cortex	UBERON:0001870	66.98	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	66.77	gold quality
small intestine	UBERON:0002108	66.56	gold quality
neocortex	UBERON:0001950	66.24	gold quality
right testis	UBERON:0004534	65.80	gold quality
testis	UBERON:0000473	64.88	gold quality
telencephalon	UBERON:0001893	64.58	gold quality
forebrain	UBERON:0001890	62.92	gold quality
islet of Langerhans	UBERON:0000006	62.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	62.27	gold quality
cerebral cortex	UBERON:0000956	62.22	gold quality
skin of leg	UBERON:0001511	61.48	gold quality
diaphragm	UBERON:0001103	60.82	gold quality
skin of abdomen	UBERON:0001416	59.99	gold quality
orbitofrontal cortex	UBERON:0004167	59.84	gold quality
amygdala	UBERON:0001876	59.48	gold quality
brain	UBERON:0000955	59.35	gold quality
zone of skin	UBERON:0000014	58.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HR, REST

miRNA regulators (miRDB)

9 targeting CHRM4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-5587-5P	99.07	68.58	838
HSA-MIR-4468	98.01	66.85	1187
HSA-MIR-1226-3P	97.51	66.32	1063

Literature-anchored findings (GeneRIF, showing 16)

• relative to other muscarinic receptor subtypes, the M(4) receptor could be the subtype which is selectively compromised in Alzeheimer’s disease (PMID:12505680)
• M4 increases expression of “migratory” integrins; M4 effects resulted from inhibition of the inhibitory pathway involving the adenylyl cyclase-cyclic AMP-protein kinase A pathway (PMID:15263021)
• In progressive supranuclear palsy: there were no changes in M4 muscarinic receptor density (PMID:18282687)
• Regions in i3 including Leu272-Arg338 and Val373-Ala393 are involved in internalization of the M4 receptor; the region including Val373-Ala393 is indispensable for its recycling, whereas the other regions are dispensable for internalization and recycling. (PMID:18337477)
• analysis of allosteric agonism and modulation at the M4 muscarinic acetylcholine receptor (PMID:20406819)
• Use of HM4- and green fluorescent protein-expressing trangenic mice as tissue donors in cell-based therapy validates a rodent model of Huntington disease. (PMID:21295605)
• The data of this study suggested that the rs2067482 polymorphism may help to predict susceptibility to schizophrenia and/or therapeutic responsiveness. (PMID:23490763)
• Data indicate that compounds derived from VU0152100 showed M4 muscarinic receptor (M4 mAChR) direct agoinst properties. (PMID:24074052)
• This study identify suppression of the PVHSIM1–>PAGvl/DR circuit connection as sufficient to induce overeating behavior. (PMID:24768300)
• [(3)H]LY2119620 to probe specifically the human M2 and M4 muscarinic receptor allosteric binding sites. (PMID:24807966)
• This study demonstrated that CD4+ and CD8+ T cells expressed M2 and M4 muscarinic receptors which density were significantly increased in asthmatic children in comparison with controls. (PMID:26025056)
• crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium (PMID:26958838)
• the association of the African-specific CHRM4 SNP with cocaine dependence survived correction for multiple testing (PMID:27269905)
• Authors discuss how M4 activity regulates DA release and signaling, the potential sources of ACh that can regulate M4 activity, and the implications of targeting M4 activity for the treatment of the motor symptoms in movement disorders. [Review] (PMID:31211471)
• Group II muscarinic acetylcholine receptors attenuate hepatic injury via Nrf2/ARE pathway. (PMID:32234387)
• Muscarinic Receptors Expression in the Peripheral Blood Cells Differentiate Dementia with Lewy Bodies from Alzheimer’s Disease. (PMID:34806612)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	chrm4a	ENSDARG00000069254
mus_musculus	Chrm4	ENSMUSG00000040495
rattus_norvegicus	Chrm4	ENSRNOG00000017556

Paralogs (25): DRD4 (ENSG00000069696), HRH3 (ENSG00000101180), HRH2 (ENSG00000113749), CHRM3 (ENSG00000133019), HRH4 (ENSG00000134489), TAAR5 (ENSG00000135569), GPR84 (ENSG00000139572), GPR161 (ENSG00000143147), TAAR2 (ENSG00000146378), TAAR6 (ENSG00000146383), TAAR8 (ENSG00000146385), TAAR1 (ENSG00000146399), DRD3 (ENSG00000151577), HTR4 (ENSG00000164270), CHRM1 (ENSG00000168539), DRD5 (ENSG00000169676), HTR1A (ENSG00000178394), HTR1D (ENSG00000179546), CHRM2 (ENSG00000181072), DRD1 (ENSG00000184845), CHRM5 (ENSG00000184984), GPR21 (ENSG00000188394), HRH1 (ENSG00000196639), GPR52 (ENSG00000203737), TAAR9 (ENSG00000237110)

Protein

Protein identifiers

Muscarinic acetylcholine receptor M4 — P08173 (reviewed: P08173)

All UniProt accessions (1): P08173

UniProt curated annotations — full annotation on UniProt →

Function. The muscarinic acetylcholine receptor mediates various cellular responses, including inhibition of adenylate cyclase, breakdown of phosphoinositides and modulation of potassium channels through the action of G proteins. Primary transducing effect is inhibition of adenylate cyclase.

Subcellular location. Cell membrane. Postsynaptic cell membrane.

Similarity. Belongs to the G-protein coupled receptor 1 family. Muscarinic acetylcholine receptor subfamily. CHRM4 sub-subfamily.

RefSeq proteins (2): NP_000732, NP_001353621 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000995	Musac_Ach_rcpt	Family
IPR001432	Musac_Ach_M4_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (46 total): helix 15, topological domain 8, transmembrane region 7, strand 4, modified residue 3, compositionally biased region 2, glycosylation site 2, turn 2, chain 1, region of interest 1, disulfide bond 1

Structure

Experimental structures (PDB)

37 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
7TRP	ELECTRON MICROSCOPY	2.4
8FX5	ELECTRON MICROSCOPY	2.45
7TRQ	ELECTRON MICROSCOPY	2.5
9N09	ELECTRON MICROSCOPY	2.57
5DSG	X-RAY DIFFRACTION	2.6
8E9X	ELECTRON MICROSCOPY	2.7
9KVP	ELECTRON MICROSCOPY	2.79
7TRK	ELECTRON MICROSCOPY	2.8
7TRS	ELECTRON MICROSCOPY	2.8
9KV6	ELECTRON MICROSCOPY	2.88
6KP6	X-RAY DIFFRACTION	3
9KUG	ELECTRON MICROSCOPY	3.07
9KX6	ELECTRON MICROSCOPY	3.11
9KWX	ELECTRON MICROSCOPY	3.13
9KWG	ELECTRON MICROSCOPY	3.15
9UMR	ELECTRON MICROSCOPY	3.15
9KV8	ELECTRON MICROSCOPY	3.17
7LD3	ELECTRON MICROSCOPY	3.2
9UMX	ELECTRON MICROSCOPY	3.2
9KUT	ELECTRON MICROSCOPY	3.29
7LD4	ELECTRON MICROSCOPY	3.3
8IYH	ELECTRON MICROSCOPY	3.3
9KZ8	ELECTRON MICROSCOPY	3.3
9KXS	ELECTRON MICROSCOPY	3.31
8IY9	ELECTRON MICROSCOPY	3.37
9UMJ	ELECTRON MICROSCOPY	3.38
7V68	ELECTRON MICROSCOPY	3.4
7V69	ELECTRON MICROSCOPY	3.4
9KZ2	ELECTRON MICROSCOPY	3.43
8IYW	ELECTRON MICROSCOPY	3.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08173-F1	76.06	0.53

Antibody-complex structures (SAbDab): 27 — 7TRK, 7TRP, 7TRQ, 7TRS, 7V68, 7V69, 7V6A, 8E9X, 8FX5, 8IY9, 8IYH, 8IYW, 8JER, 8JHN, 9KUG, 9KV6, 9KV8, 9KWG, 9KWX, 9KX6, 9KXS, 9KZ2, 9KZ8, 9KZK, 9UMJ (+2 more)

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 459, 463, 477

Disulfide bonds (1): 105–185

Glycosylation sites (2): 8, 13

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-390648	Muscarinic acetylcholine receptors
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-375280	Amine ligand-binding receptors
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 99 (showing top): RNGTGGGC_UNKNOWN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, ROVERSI_GLIOMA_COPY_NUMBER_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELL_CELL_SIGNALING, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SYNAPTIC_SIGNALING, GOBP_RESPONSE_TO_ACETYLCHOLINE, PU1_Q6, GOBP_ADENYLATE_CYCLASE_INHIBITING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOCC_NEURON_PROJECTION, LEE_CALORIE_RESTRICTION_NEOCORTEX_DN

GO Biological Process (8): signal transduction (GO:0007165), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway (GO:0007197), G protein-coupled acetylcholine receptor signaling pathway (GO:0007213), chemical synaptic transmission (GO:0007268), regulation of locomotion (GO:0040012), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (2): G protein-coupled acetylcholine receptor activity (GO:0016907), G protein-coupled receptor activity (GO:0004930)

GO Cellular Component (5): plasma membrane (GO:0005886), dendrite (GO:0030425), synapse (GO:0045202), postsynaptic membrane (GO:0045211), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Signaling by GPCR	2
Amine ligand-binding receptors	1
GPCR downstream signalling	1
Signal Transduction	1
GPCR ligand binding	1
Class A/1 (Rhodopsin-like receptors)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	3
signal transduction	2
G protein-coupled acetylcholine receptor signaling pathway	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	1
G protein-coupled acetylcholine receptor activity	1
acetylcholine receptor signaling pathway	1
anterograde trans-synaptic signaling	1
locomotion	1
regulation of biological process	1
G protein-coupled receptor activity	1
G protein-coupled amine receptor activity	1
acetylcholine receptor activity	1
G protein-coupled neurotransmitter receptor activity	1
transmembrane signaling receptor activity	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
cell junction	1
synaptic membrane	1
postsynapse	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHRM4	ARRB1	P49407	532
CHRM4	RIC8B	Q9NVN3	519
CHRM4	CHRNB2	P17787	496
CHRM4	APOL2	Q9BQE5	490
CHRM4	APOL4	Q9BPW4	490
CHRM4	ARRB2	P32121	480
CHRM4	PDE4B	Q07343	468
CHRM4	SYN2	Q92777	453
CHRM4	GRM3	Q14832	451
CHRM4	CHRNA5	P30532	445
CHRM4	CACNA1C	Q13936	435
CHRM4	CHAT	P28329	427
CHRM4	APOL1	O14791	425
CHRM4	CHRNB4	P30926	420
CHRM4	CHRNA3	P32297	418

IntAct

42 interactions, top by confidence:

A	B	Type	Score
CHRM4	GNAI2	psi-mi:“MI:0915”(physical association)	0.490
HTR2C	CHRM4	psi-mi:“MI:0915”(physical association)	0.470
HTR2C	CHRM4	psi-mi:“MI:2364”(proximity)	0.470
CHRM4	SH3GL1	psi-mi:“MI:0915”(physical association)	0.400
SH3GL2	CHRM4	psi-mi:“MI:0915”(physical association)	0.400
CHRM4	SH3GL3	psi-mi:“MI:0915”(physical association)	0.400
	CHRM4	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	CHRM4	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	CHRM4	psi-mi:“MI:0915”(physical association)	0.400
CHRM4	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
CHRM4	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	CHRM4	psi-mi:“MI:0915”(physical association)	0.400
CHRM4	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
MFSD4A	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
TSPAN7	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
YIPF3	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
RHBDD2	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
ERGIC3	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
CD59	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
RAB3A	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
METTL9	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
B2M	CHRM4	psi-mi:“MI:0915”(physical association)	0.370
SMIM7	CHRM4	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (132): USP24 (Affinity Capture-MS), PDS5B (Affinity Capture-MS), PPP1R15B (Affinity Capture-MS), GSPT1 (Affinity Capture-MS), PDXDC1 (Affinity Capture-MS), CAND2 (Affinity Capture-MS), XPO6 (Affinity Capture-MS), LPCAT3 (Affinity Capture-MS), THADA (Affinity Capture-MS), IPO9 (Affinity Capture-MS), SARM1 (Affinity Capture-MS), HEATR3 (Affinity Capture-MS), IPO11 (Affinity Capture-MS), EFR3A (Affinity Capture-MS), TUBB3 (Affinity Capture-MS)

ESM2 similar proteins: O42490, P04761, P08173, P08482, P08485, P08911, P08912, P08913, P11229, P11617, P12657, P15823, P17200, P18089, P18841, P22909, P29274, P30543, P30546, P30729, P31389, P32211, P35368, P41984, P43140, P46616, P47901, P48974, P56489, P56490, P70174, Q01338, Q28838, Q5IS53, Q5IS98, Q5R949, Q5XXP2, Q5YKK9, Q60474, Q60475

Diamond homologs: A1ZAX0, A5A4K9, A5A4L1, F1MV99, O02664, O08725, O08858, O19014, O43193, O55040, O77723, O88319, O88634, O88855, O97772, P06199, P08172, P08173, P08485, P10980, P17200, P19020, P20288, P20789, P20905, P21917, P28646, P30372, P30729, P30872, P30873, P30937, P30938, P30989, P31391, P32211, P32300, P32745, P33533, P33534

SIGNOR signaling

19 interactions.

A	Effect	B	Mechanism
CHRM4	“up-regulates activity”	GNAI1	binding
CHRM4	“up-regulates activity”	GNAI3	binding
CHRM4	“up-regulates activity”	GNAO1	binding
acetylcholine	“up-regulates activity”	CHRM4	“chemical activation”
sabcomeline	“up-regulates activity”	CHRM4	“chemical activation”
atropine	“down-regulates activity”	CHRM4	“chemical inhibition”
Hexocyclium	“down-regulates activity”	CHRM4	“chemical inhibition”
carbachol	“up-regulates activity”	CHRM4	“chemical activation”
bethanechol	“up-regulates activity”	CHRM4	“chemical activation”
(+)-pilocarpine	“up-regulates activity”	CHRM4	“chemical activation”
“1-methyl-3,6-dihydro-2H-pyridine-5-carboxylic acid prop-2-ynyl ester”	“up-regulates activity”	CHRM4	“chemical activation”
arecoline	“up-regulates activity”	CHRM4	“chemical activation”
furtrethonium	“up-regulates activity”	CHRM4	“chemical activation”
trimethyl-[(5-methyl-2-furanyl)methyl]ammonium	“up-regulates activity”	CHRM4	“chemical activation”
Oxotremorine	“up-regulates activity”	CHRM4	“chemical activation”
“oxotremorine M”	“up-regulates activity”	CHRM4	“chemical activation”
dothiepin	“down-regulates activity”	CHRM4	“chemical inhibition”
amitriptyline	“down-regulates activity”	CHRM4	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 29 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to plasma membrane	5	20.9×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

54 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	51
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
3906920	GRCh37/hg19 11p11.2(chr11:45873734-46409298)x1	Pathogenic
979915	GRCh37/hg19 11p11.2(chr11:45995260-46536343)x1	Likely pathogenic

SpliceAI

5 predictions. Top by Δscore:

Variant	Effect	Δscore
11:46385505:ATTG:A	donor_gain	0.3200
11:46385399:TGCGC:T	donor_gain	0.2300
11:46385737:T:TA	donor_gain	0.2100
11:46385336:C:CC	acceptor_gain	0.2000
11:46385375:C:CA	donor_gain	0.2000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000159355 (11:46386758 C>G,T), RS1000209568 (11:46386312 G>A,T), RS1000320104 (11:46387010 G>A), RS1000367392 (11:46392958 T>C,G), RS1000432242 (11:46393238 T>C), RS1000644077 (11:46391288 G>A,T), RS1000768361 (11:46392106 G>A,C,T), RS1001164681 (11:46388087 C>T), RS1001216819 (11:46387927 G>A,C,T), RS1001450203 (11:46384770 AG>A), RS1003161715 (11:46388318 T>C,G), RS1003395780 (11:46383404 C>A,G,T), RS1003540526 (11:46389591 G>C,T), RS1003547244 (11:46386727 G>A,T), RS1003751040 (11:46383585 T>C,G)

Disease associations

OMIM: gene MIM:118495 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004521_122	Autism spectrum disorder or schizophrenia	3.000000e-13
GCST004521_165	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004946_84	Schizophrenia	7.000000e-12
GCST006803_20	Schizophrenia	3.000000e-13
GCST007825_4	Alzheimer’s disease or fasting glucose levels (pleiotropy)	3.000000e-16

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1821 (SINGLE PROTEIN), CHEMBL2094109 (PROTEIN FAMILY), CHEMBL2111445 (SELECTIVITY GROUP)

Molecules with ChEMBL bioactivity

106 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 310,359 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1092	TRIHEXYPHENIDYL HYDROCHLORIDE	4	7,793
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1101	BIPERIDEN	4	11,044
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL1172	DESLORATADINE	4	19,720
CHEMBL1200406	DIMENHYDRINATE	4	26,424
CHEMBL1200604	TROPICAMIDE	4	14,498
CHEMBL1201027	GLYCOPYRRONIUM BROMIDE	4	14,355
CHEMBL1201203	BENZTROPINE	4	9,334
CHEMBL1201207	BETAMETHASONE PHOSPHORIC ACID	4	954
CHEMBL1201217	DYCLONINE	4	7,785
CHEMBL1201353	DEXCHLORPHENIRAMINE	4	8,566
CHEMBL1221	SULCONAZOLE	4	12,121
CHEMBL1231	OXYBUTYNIN	4	15,072
CHEMBL1319362	HOMATROPINE HYDROBROMIDE	4	1,442
CHEMBL1346	DARIFENACIN	4	8,259
CHEMBL1354199	METHSCOPOLAMINE BROMIDE	4	2,067
CHEMBL1382	TOLTERODINE	4
CHEMBL14	CARBACHOL	4
CHEMBL1490	TRIHEXYPHENIDYL	4
CHEMBL1529	DIPHENIDOL HYDROCHLORIDE	4
CHEMBL1535	HYDROXYCHLOROQUINE	4
CHEMBL1621597	IPRATROPIUM	4
CHEMBL1626	CLEMASTINE	4
CHEMBL1628227	DOXEPIN	4
CHEMBL1633	KETOTIFEN FUMARATE	4
CHEMBL168815	CEVIMELINE	4

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2067482	CHRM4		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Acetylcholine receptors (muscarinic)

Most potent curated ligand interactions (94 total), top 25:

Ligand	Action	Affinity	Parameter
tiotropium	Antagonist	10.6	pKi
[3H]QNB	Antagonist	10.5	pKd
3-quinuclidinyl-benzilate	Antagonist	10.4	pKi
umeclidinium	Antagonist	10.3	pKi
[3H]N-methyl scopolamine	Antagonist	10.22	pKd
propantheline	Antagonist	10.2	pKi
[3H]iperoxo	Agonist	10.1	pKd
aclidinium	Antagonist	10.0	pKi
glycopyrrolate	Antagonist	10.0	pKi
oxyphenonium	Antagonist	9.84	pKi
atropine	Antagonist	9.5	pKi
scopolamine	Antagonist	9.5	pKi
AE9C90CB	Antagonist	9.5	pKi
mepenzolic acid	Antagonist	9.44	pKi
revefenacin	Antagonist	9.26	pKi
ipratropium	Antagonist	9.2	pKi
4-DAMP	Antagonist	8.9	pKi
pentylthio-TZTP	Full agonist	8.7	pKi
muscarinic toxin 3	Negative	8.7	pKi
oxybutynin	Antagonist	8.7	pKi
[3H]AF DX-384	Antagonist	8.7	pKd
biperiden	Antagonist	8.62	pKd
NNC 11-1585	Full agonist	8.6	pKi
silahexocyclium	Antagonist	8.5	pKi
tolterodine	Antagonist	8.4	pKi

Binding affinities (BindingDB)

171 measured of 246 human assays (275 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
NNC 11-1585	KI	0.129 nM
(2S,4aR,6aR,7R,9S,10aS,10bR)-9-(acetyloxy)-2-(furan-3-yl)dodecahydro-6a,10b-dimethyl-4,10-dioxo-2H-naphtho-[2,1-c]pyran-7-carboxylic acid methyl ester	EC50	0.3 nM
1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-(piperidin-1-yl)propan-1-ol	KI	0.48 nM
NSC_3746	KI	0.49 nM
2-Chlor-11-(2-dimethylaminoaethoxy)-dibenzo(b,f)-thiepin	KI	0.5 nM
4-Diphenylacetoxy-1,1-dimethyl-piperidinium; iodide	KI	0.58 nM
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine	KI	0.6 nM
CAS_62865	KI	1.5 nM
NSC_132947	KI	1.58 nM
CHEMBL195011	EC50	1.74 nM
5-[2-(4-Benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-6-chloro-1,3-dihydro-indol-2-one	KI	1.9 nM
ethyl 4-[4-(5-chloro-2-methoxy-3-pyridinyl)piperidin-1-yl]azepane-1-carboxylate	EC50	2 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
NNC 11-1607	KI	2.4 nM
4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one;propionate(HCl)	KI	2.92 nM
ATR	IC50	3.2 nM	US-9333195: Quinuclidine derivatives and medicinal compositions containing the same
1-Cyclohexyl-1-phenyl-3-pyrrolidin-1-yl-propan-1-ol	KI	4.6 nM
CHEMBL196218	EC50	4.79 nM
Enablex	KI	5.5 nM
CHEMBL194008	EC50	6.46 nM
HHSiD	KI	14 nM
ethyl 4-[4-(2-ethoxy-5-methyl-3-pyridinyl)piperidin-1-yl]azepane-1-carboxylate	EC50	20 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
ethyl 4-[4-[2-[(3-methyl-1,2-oxazol-5-yl)methoxy]-3-pyridinyl]piperidin-1-yl]azepane-1-carboxylate	EC50	20 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
ethyl 4-[4-[2-(1,3-thiazol-4-ylmethoxy)-3-pyridinyl]piperidin-1-yl]azepane-1-carboxylate	EC50	22 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
CAS_5311091	KI	22.4 nM
ethyl (4S)-4-[4-(2-methoxy-3-pyridinyl)piperidin-1-yl]azepane-1-carboxylate	EC50	26 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
NSC_2054314	KI	26.3 nM
CHEMBL364454	EC50	26.9 nM
NSC_129989	KI	28.8 nM
ethyl 4-[4-(2-methoxy-3-pyridinyl)piperidin-1-yl]azepane-1-carboxylate	EC50	30 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
NSC_119356	KI	30.9 nM
1-(4-{3-[4-(6-Fluoro-benzo[d]isoxazol-3-yl)-piperidin-1-yl]-propoxy}-3-methoxy-phenyl)-ethanone	KI	33 nM
Fluorocarazolol,(S)	KI	34 nM
NNC 11-1314	KI	41.7 nM
CHEMBL194793	EC50	44.7 nM
Dimethyl-[2-(phenyl-o-tolyl-methoxy)-ethyl]-amine	KI	48 nM
CHEMBL372536	EC50	50.1 nM
LY 246708	KI	50.1 nM
5-(1-methylpiperidylidene-4)-5H-dibenzo(a,d)cyclopheptene	KI	59 nM
ethyl 4-[4-(2-ethoxy-3-pyridinyl)piperidin-1-yl]azepane-1-carboxylate	EC50	60 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
CHEMBL197092	EC50	79.4 nM
ethyl (4S)-4-(4-pyrazol-1-ylpiperidin-1-yl)azepane-1-carboxylate	EC50	85 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
NSC_40589	KI	85 nM
CHEMBL194196	EC50	89.1 nM
ethyl 4-[4-(2-methoxy-3-pyridinyl)piperidin-1-yl]piperidine-1-carboxylate	EC50	90 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists
3-[4-(2-Methyl-1H-imidazol-1-yl)-2-butynyl]oxy-delta2-isoxazoline sesquifumarate	KI	91.2 nM
CHEMBL196151	EC50	93.3 nM
2-{3-[4-(3-chlorophenyl)piperazin-1-yl]propyl}[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one	KI	96 nM
CHEMBL373341	EC50	104 nM
HIMBACINE	KI	107 nM
ethyl 4-[4-(2-cyclopropyl-3-pyridinyl)piperidin-1-yl]azepane-1-carboxylate	EC50	120 nM	US-10030012: Piperidin-1-yl and azepin-1-yl carboxylates as muscarinic M4 receptor agonists

ChEMBL bioactivities

2971 potent at pChembl≥5 of 3160 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.92	Kd	0.01202	nM	CHEMBL318812
10.46	Kd	0.03467	nM	CHEMBL320611
10.40	IC50	0.03981	nM	TIOTROPIUM BROMIDE
10.35	Ki	0.045	nM	QUINUCLIDINYL BENZILATE
10.30	ED50	0.05	nM	ATROPINE
10.29	Ki	0.051	nM	QUINUCLIDINYL BENZILATE
10.28	Kd	0.052	nM	CHEMBL4860528
10.28	Kd	0.052	nM	CHEMBL5207281
10.28	Kd	0.052	nM	CHEMBL5206565
10.28	Kd	0.052	nM	CHEMBL5201074
10.27	Ki	0.054	nM	CHEMBL320611
10.15	Ki	0.07	nM	CHEMBL71124
10.05	Ki	0.09	nM	CHEMBL2114068
10.01	Ki	0.098	nM	METHSCOPOLAMINE BROMIDE
9.98	Ki	0.104	nM	ATROPINE
9.94	Ki	0.115	nM	PF-03635659
9.85	Ki	0.1413	nM	METHSCOPOLAMINE
9.82	ED50	0.15	nM	ATROPINE
9.80	IC50	0.1585	nM	GLYCOPYRRONIUM BROMIDE
9.70	Ki	0.2	nM	QUINUCLIDINYL BENZILATE
9.70	IC50	0.1995	nM	ACLIDINIUM BROMIDE
9.62	Ki	0.24	nM	QUINUCLIDINYL BENZILATE
9.57	Ki	0.27	nM	CHEMBL331497
9.57	Ki	0.27	nM	AZAPROPHEN
9.56	Ki	0.278	nM	OXYBUTYNIN
9.55	Ki	0.279	nM	CHEMBL320611
9.52	AC50	0.3	nM	TIOTROPIUM BROMIDE
9.52	Kd	0.302	nM	CHEMBL321214
9.49	Ki	0.32	nM	CHEMBL2115128
9.49	Ki	0.32	nM	ATROPINE
9.48	Ki	0.33	nM	CHEMBL71147
9.48	Ki	0.333	nM	BENZTROPINE
9.47	Ki	0.34	nM	ATROPINE
9.46	Ki	0.35	nM	CHEMBL3629360
9.43	Ki	0.37	nM	4-DAMP
9.42	Ki	0.382	nM	CHEMBL1908368
9.40	IC50	0.4	nM	CARBACHOL
9.39	Ki	0.411	nM	DICYCLOMINE
9.38	Ki	0.4169	nM	CHEMBL4742721
9.37	IC50	0.4266	nM	CHEMBL4861863
9.37	IC50	0.43	nM	CHEMBL4861863
9.36	IC50	0.44	nM	CHEMBL4853244
9.35	Ki	0.4467	nM	CHEMBL4636083
9.35	Kd	0.4467	nM	CHEMBL321214
9.35	Ki	0.449	nM	CHEMBL318812
9.33	Ki	0.4677	nM	CHEMBL375969
9.33	Ki	0.4677	nM	CHEMBL4097258
9.32	Ki	0.475	nM	CHEMBL321214
9.31	IC50	0.49	nM	4-DAMP
9.29	Ki	0.5129	nM	4-DAMP

PubChem BioAssay actives

2353 with measured affinity, of 5673 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
Tiotropium Bromide Monohydrate	539982: Displacement of [3H]NMS from human muscarinic M4 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay	ic50	<0.0001	uM
[(3S)-6-methyl-6-azabicyclo[3.2.1]octan-3-yl] 2,2-diphenylpropanoate	73701: Inhibition of methacholine induced phasic contraction of guinea pig ileum	kd	<0.0001	uM
[(3S)-6-methyl-6-azabicyclo[3.2.1]octan-3-yl] 2-hydroxy-2,2-diphenylacetate	73701: Inhibition of methacholine induced phasic contraction of guinea pig ileum	kd	<0.0001	uM
1-azabicyclo[2.2.2]octan-3-yl 2-hydroxy-2,2-diphenylacetate	141150: Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in the heart from Guinea Pig.	ki	<0.0001	uM
1-cyclohexyl-4-[1-[4-(4-methoxyphenyl)sulfinylphenyl]ethyl]piperidine	141888: Binding affinity against Muscarinic acetylcholine receptor M4	ki	0.0001	uM
5-[3-(3-hydroxyphenoxy)azetidin-1-yl]-5-methyl-2,2-diphenylhexanamide	627081: Displacement of [3H]-NMS from human recombinant M4 receptor expressed in CHO cells after 24 hrs by filter binding assay	ki	0.0001	uM
1-[N’-[3-(2-amino-4-methyl-1,3-thiazol-5-yl)propyl]carbamimidoyl]-3-pentylurea	1895229: Displacement of [3H]N-methylscopolamine from human muscarinic acetylcholine M4 receptor stably expressed in CHO cells by radioligand competition binding based analysis	kd	0.0001	uM
1-[(1R)-1-phenylethyl]-3-[N’-[3-(1H-1,2,4-triazol-5-yl)propyl]carbamimidoyl]urea;dihydrochloride	1895229: Displacement of [3H]N-methylscopolamine from human muscarinic acetylcholine M4 receptor stably expressed in CHO cells by radioligand competition binding based analysis	kd	0.0001	uM
1-[N’-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]carbamimidoyl]-3-pentylurea;bis(2,2,2-trifluoroacetic acid)	1895229: Displacement of [3H]N-methylscopolamine from human muscarinic acetylcholine M4 receptor stably expressed in CHO cells by radioligand competition binding based analysis	kd	0.0001	uM
1-[N’-[3-(5-amino-1,3,4-thiadiazol-2-yl)propyl]carbamimidoyl]-3-benzylurea;bis(2,2,2-trifluoroacetic acid)	1895229: Displacement of [3H]N-methylscopolamine from human muscarinic acetylcholine M4 receptor stably expressed in CHO cells by radioligand competition binding based analysis	kd	0.0001	uM
[(1S,2S,4R,5R)-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4]nonan-7-yl] (2S)-3-hydroxy-2-phenylpropanoate	280354: Binding affinity to human cloned muscarinic receptor M4 expressed in CHO cells	ki	0.0001	uM
1-cyclohexyl-4-[1-[4-[(R)-(4-methoxyphenyl)sulfinyl]phenyl]ethenyl]piperidine	141888: Binding affinity against Muscarinic acetylcholine receptor M4	ki	0.0001	uM
Aclidinium Bromide	539982: Displacement of [3H]NMS from human muscarinic M4 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay	ic50	0.0002	uM
Glycopyrrolate	539982: Displacement of [3H]NMS from human muscarinic M4 receptor expressed in CHO-K1 cells after 16 hrs by scintillation proximity assay	ic50	0.0002	uM
3-[2-(1-azabicyclo[2.2.2]oct-2-en-3-yl)furan-3-yl]phenol	141149: Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in cerebral cortex from Guinea Pig.	ki	0.0003	uM
(6-methyl-6-azabicyclo[3.2.1]octan-3-yl) 2,2-diphenylpropanoate	141400: Inhibit the binding of [N-mnethyl-3H]-scopolamine [3H]-NMS) to Muscarinic acetylcholine receptor of human IRM-30 neuroblastoma cells	ki	0.0003	uM
[(1S,5R)-8-methyl-8-azabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate	141149: Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in cerebral cortex from Guinea Pig.	ki	0.0003	uM
[(3R)-6-methyl-6-azabicyclo[3.2.1]octan-3-yl] 2-hydroxy-2,2-diphenylacetate	73701: Inhibition of methacholine induced phasic contraction of guinea pig ileum	kd	0.0003	uM
5-[(1R)-2-[2-[4-[2-[4-[[3-[(R)-cyclohexyl-hydroxy-phenylmethyl]-1,2,4-triazol-1-yl]methyl]piperidin-1-yl]ethyl]phenyl]ethylamino]-1-hydroxyethyl]-8-hydroxy-1H-quinolin-2-one	1253955: Antagonist activity at muscarinic M4 receptor (unknown origin)	ki	0.0003	uM
1-cyclohexyl-4-[1-[4-[(S)-(4-methoxyphenyl)sulfinyl]phenyl]ethenyl]piperidine	141888: Binding affinity against Muscarinic acetylcholine receptor M4	ki	0.0003	uM
1-cyclohexyl-4-[1-[4-(4-methoxyphenyl)sulfonylphenyl]ethenyl]piperidine	141888: Binding affinity against Muscarinic acetylcholine receptor M4	ki	0.0003	uM
11-[2-[4-[4-[4-(2-aminoethyl)piperazin-1-yl]butyl]piperidin-1-yl]acetyl]-5H-benzo[b][1,4]benzodiazepin-6-one;tetrakis(2,2,2-trifluoroacetic acid)	1648504: Displacement of [3H]-NMS from human muscarinic M4 receptor stably expressed in CHO-K9 cells by radioligand competitive binding assay	ki	0.0004	uM
(3aR,6aS)-N-[6-(2-methylindazol-5-yl)pyridazin-3-yl]-2-(oxan-4-ylmethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-amine	1779707: Displacement of [3H]NMS from human muscarinic receptor M4 expressed in CHO cell membranes incubated for 3 hrs by radiometric scintillation counting analysis	ic50	0.0004	uM
6-[[2-[4-[(E)-2-(2,2-difluoro-12-thiophen-2-yl-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-1(12),4,6,8,10-pentaen-4-yl)ethenyl]phenoxy]acetyl]amino]-N-[2-[3-[1-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]imidazol-4-yl]propanoylamino]ethyl]hexanamide;bis(2,2,2-trifluoroacetic acid)	1710660: Displacement of [3H]NMS from human recombinant muscarinic receptor M4 expressed in CHO-K9 cell membranes measured after 3 hrs by radioligand competition binding assay	ki	0.0004	uM
(3aR,6aS)-N-[6-(2-chloro-5-fluorophenyl)pyridazin-3-yl]-2-[dideuterio(oxan-4-yl)methyl]-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-amine	1779716: Antagonist activity at human muscarinic acetylcholine M4 receptor expressed in CHO cells assessed as inhibition of acetylcholine-induced calcium mobilization	ic50	0.0004	uM
(1,1-dimethylpiperidin-1-ium-4-yl) 2,2-diphenylacetate iodide	751873: Binding affinity to human muscarinic M4 receptor by radioligand displacement assay	ki	0.0004	uM
(8-methyl-8-propan-2-yl-8-azoniabicyclo[3.2.1]octan-3-yl) 3-hydroxy-2-phenylpropanoate;bromide;hydrate	627081: Displacement of [3H]-NMS from human recombinant M4 receptor expressed in CHO cells after 24 hrs by filter binding assay	ki	0.0004	uM
Carbachol	142556: Compound was evaluated for its binding affinity at human muscarinic receptor m4 by the displacement of [3H]NMS radioligand using membranes from transfected chinese hamster ovarian cell	ic50	0.0004	uM
1-N,3-N-bis[2-[3-[1-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]imidazol-4-yl]propanoylamino]ethyl]-5-[(propanoylamino)methyl]benzene-1,3-dicarboxamide;tetrakis(2,2,2-trifluoroacetic acid)	1482271: Displacement of [3H]NMS from human muscarinic acetylcholine receptor M4 expressed in CHOK9 cells after 3 hrs by liquid scintillation counting assay	ki	0.0005	uM
(2S)-2-[(5S)-2,2-diphenyl-1,3-oxathiolan-5-yl]-1,1-dimethylpyrrolidin-1-ium iodide	280354: Binding affinity to human cloned muscarinic receptor M4 expressed in CHO cells	ki	0.0005	uM
3-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-4-[10-[[4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazol-3-yl]sulfanyl]decylsulfanyl]-1,2,5-thiadiazole	141866: Agonist activity against M4 muscarinic receptor expressed in RBL-2H3 Mast cells.	ec50	0.0006	uM
[(1S,2S,4S,5R)-9-methyl-3-oxa-9-azatricyclo[3.3.1.02,4]nonan-7-yl] (2S)-3-hydroxy-2-phenylpropanoate	1479900: Antagonist activity at human SP/Myc epitope-tagged muscarinic M4 receptor expressed in HEK293T cells assessed as inhibition of carbachol-induced mVenus-fused beta-arrestin2 recruitment preincubated for 15 mins followed by carbachol induction measured after 2 mins by BRET assay	ic50	0.0006	uM
(3aS,6aR)-N-[6-(2-chloro-5-fluorophenyl)pyridazin-3-yl]-2-(oxan-4-ylmethyl)-3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-5-amine	1779716: Antagonist activity at human muscarinic acetylcholine M4 receptor expressed in CHO cells assessed as inhibition of acetylcholine-induced calcium mobilization	ic50	0.0006	uM
[1-[8-[6-[(2Z)-3,3-dimethyl-2-[(2E,4E)-5-(1,3,3-trimethylindol-1-ium-2-yl)penta-2,4-dienylidene]indol-1-yl]hexanoylamino]octyl]piperidin-4-yl]methyl N-[2-(3-chloro-4-fluorophenyl)-4-fluorophenyl]carbamate	1936436: Displacement of [3H]N-methylscopolamine from human muscarinic M4 receptor expressed in human HEK293T cell membranes by radioligand competition binding based analysis	ki	0.0006	uM
5-[(2,3-ditritiopropanoylamino)methyl]-1-N,3-N-bis[2-[3-[1-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]imidazol-4-yl]propanoylamino]ethyl]benzene-1,3-dicarboxamide;tetrakis(2,2,2-trifluoroacetic acid)	1482281: Binding affinity to human muscarinic acetylcholine receptor M4 expressed in CHOK9 cells after 2 hrs by liquid scintillation counting assay	kd	0.0007	uM
(2R)-2-[(2R,5R)-2-cyclohexyl-2-phenyl-1,3-oxathiolan-5-yl]-1,1-dimethylpyrrolidin-1-ium iodide	280354: Binding affinity to human cloned muscarinic receptor M4 expressed in CHO cells	ki	0.0007	uM
(2S)-N-[(2S)-1-[[(2S)-1-acetamido-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]-5-(diaminomethylideneamino)-2-[2-[4-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]piperazin-1-yl]ethylamino]pentanamide;pentakis(2,2,2-trifluoroacetic acid)	1756789: Displacement of [3H]-NMS from human muscarinic M4 receptor expressed in CHO cell membranes assessed as inhibition constant by radioligand competition analysis	ki	0.0007	uM
(2S)-N-acetyl-5-(diaminomethylideneamino)-2-[[(2S)-2-[[2-[2-[4-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]piperazin-1-yl]ethylamino]acetyl]amino]propanoyl]amino]pentanamide;tetrakis(2,2,2-trifluoroacetic acid)	1756789: Displacement of [3H]-NMS from human muscarinic M4 receptor expressed in CHO cell membranes assessed as inhibition constant by radioligand competition analysis	ki	0.0007	uM
(2S)-N-[2-[[(2S)-1-[[(2S)-1-acetamido-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]-5-(diaminomethylideneamino)-2-[2-[4-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]piperazin-1-yl]ethylamino]pentanamide;pentakis(2,2,2-trifluoroacetic acid)	1756789: Displacement of [3H]-NMS from human muscarinic M4 receptor expressed in CHO cell membranes assessed as inhibition constant by radioligand competition analysis	ki	0.0007	uM
[(2S,6S)-6-cyclohexyl-6-phenyl-1,4-dioxan-2-yl]methyl-trimethylazanium iodide	1654800: Displacement of [3H]NMS from human recombinant muscarinic receptor M4 expressed in CHO-K1 cell membranes incubated for 2 hrs by scintillation counting method	ki	0.0007	uM
4-[2-(1-azabicyclo[2.2.2]oct-2-en-3-yl)furan-3-yl]phenol	141149: Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in cerebral cortex from Guinea Pig.	ki	0.0008	uM
1-[(2S,6S)-6-cyclohexyl-6-phenyl-1,4-dioxan-2-yl]-N,N-dimethylmethanamine	1654800: Displacement of [3H]NMS from human recombinant muscarinic receptor M4 expressed in CHO-K1 cell membranes incubated for 2 hrs by scintillation counting method	ki	0.0008	uM
(2S)-2-amino-5-(diaminomethylideneamino)-N-[2-[4-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]piperazin-1-yl]ethyl]pentanamide;pentakis(2,2,2-trifluoroacetic acid)	1756789: Displacement of [3H]-NMS from human muscarinic M4 receptor expressed in CHO cell membranes assessed as inhibition constant by radioligand competition analysis	ki	0.0008	uM
methyl 3-[2-(1-azabicyclo[2.2.2]oct-2-en-3-yl)furan-3-yl]benzoate	141151: Ability of compound to displace (-)-[3H]3-Quinuclidinyl benzilate (-)-[3H]-QNB from Muscarinic acetylcholine receptors in the parotid gland from Guinea Pig.	ki	0.0008	uM
3-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-4-[9-[[4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazol-3-yl]oxy]nonoxy]-1,2,5-thiadiazole	1167231: Displacement of [3H]NMS from human M4 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay	ki	0.0008	uM
1-[3-[4-[7-[[4-(1-methyl-3,6-dihydro-2H-pyridin-5-yl)-1,2,5-thiadiazol-3-yl]oxy]heptyl]piperidin-1-yl]propyl]-3,4-dihydroquinolin-2-one	1167231: Displacement of [3H]NMS from human M4 receptor expressed in CHO cells by microplate scintillation counting based radioligand binding assay	ki	0.0009	uM
(2S)-2-[[(2S)-2-acetamido-3-(4-hydroxyphenyl)propanoyl]amino]-6-amino-N-[2-[4-[4-[1-[2-oxo-2-(6-oxo-5H-benzo[b][1,4]benzodiazepin-11-yl)ethyl]piperidin-4-yl]butyl]piperazin-1-yl]ethyl]hexanamide;tetrakis(2,2,2-trifluoroacetic acid)	1598794: Displacement of [3H]-NMS from human muscarinic M4 receptor expressed in CHO-K9 cells after 3 hrs by microbeta2 scintillation counting method	ki	0.0009	uM
(2S)-2-[(2S,5S)-2-cyclohexyl-2-phenyl-1,3-oxathiolan-5-yl]-1,1-dimethylpyrrolidin-1-ium iodide	280354: Binding affinity to human cloned muscarinic receptor M4 expressed in CHO cells	ki	0.0009	uM
(2S)-2-[(2R,5S)-2-cyclohexyl-2-phenyl-1,3-oxathiolan-5-yl]-1,1-dimethylpyrrolidin-1-ium iodide	280354: Binding affinity to human cloned muscarinic receptor M4 expressed in CHO cells	ki	0.0009	uM
(2Z)-1-[6-[8-[4-[[2-(3-chloro-4-fluorophenyl)-4-fluorophenyl]carbamoyloxy]piperidin-1-yl]octylamino]-6-oxohexyl]-2-[(2E,4E)-5-[3,3-dimethyl-1-(4-sulfobutyl)indol-1-ium-2-yl]penta-2,4-dienylidene]-3,3-dimethylindole-5-sulfonate	1936436: Displacement of [3H]N-methylscopolamine from human muscarinic M4 receptor expressed in human HEK293T cell membranes by radioligand competition binding based analysis	ki	0.0009	uM

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetylcholine	increases activity, affects reaction, increases reaction, affects cotreatment, decreases reaction (+1 more)	5
N-Methylscopolamine	affects reaction, decreases reaction, increases reaction, affects binding	5
brucine	decreases reaction, affects binding, affects reaction, increases reaction	3
trichostatin A	decreases reaction, affects expression	2
brucine N-oxide	affects binding, increases reaction, increases activity	2
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride	affects cotreatment, decreases reaction, affects binding, increases reaction	2
Pilocarpine	affects binding, increases reaction, increases expression	2
Quinuclidinyl Benzilate	affects binding, decreases reaction, affects cotreatment	2
sotorasib	affects cotreatment, decreases expression	1
5-methylfurtrethonium	affects binding, increases reaction	1
eburnamonine	affects binding, increases reaction	1
furtrethonium	affects binding, increases reaction	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
oxotremorine M	increases reaction, affects binding	1
methoctramine	affects binding, decreases reaction	1
xanomeline	affects binding, affects cotreatment, decreases reaction	1
WIN 62577	affects binding, affects cotreatment, decreases reaction	1
WIN 51708	affects binding, decreases reaction, increases reaction	1
CGP 52608	affects binding, increases reaction	1
heptane-1,7-bis-(dimethyl-3’-phthalimidopropyl)ammonium bromide	affects binding, decreases reaction	1
abrine	increases expression	1
licochalcone B	increases expression	1
trametinib	affects cotreatment, decreases expression	1
5-(3-(3-hydroxyphenoxy)azetidin-1-yl)-5-methyl-2,2-diphenylhexanamide	affects binding	1
NVP-BKM120	affects cotreatment, decreases expression	1
Tiotropium Bromide	affects binding	1
Rocuronium	affects binding, decreases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Alcuronium	affects binding, decreases reaction	1

ChEMBL screening assays

763 unique, capped per target: 520 binding, 233 functional, 9 admet, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1006039	Binding	Binding affinity to human muscarinic M4 receptor expressed in insect Sf9 cells	Nocardimicins A, B, C, D, E, and F, siderophores with muscarinic M3 receptor inhibiting activity from Nocardia sp. TP-A0674. — J Nat Prod
CHEMBL1110550	Functional	Potentiation of muscarinic M4 receptor expressed in CHO cells co-transfected with Gqi5 assessed as effect on acetylcholine-induced intracellular calcium mobilization up to 30 uM after 1 hr by FLIPR assay	Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM. — Bioorg Med Chem Lett
CHEMBL1738002	Unclassified	PUBCHEM_BIOASSAY: Late-stage radioligand binding dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Ki. (Class of assay: screening) [Related pubchem assays (depositor defined):AID1792, AID1796, AID1823, AID253	PubChem BioAssay data set

Cellosaurus cell lines

11 cell lines: 6 spontaneously immortalized cell line, 3 cancer cell line, 1 undefined cell line type, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C4TT	Chem-4 CHRM4	Undefined cell line type
CVCL_E9C4	WIZ02e-H9CAGhM4Di	Embryonic stem cell	Female
CVCL_F4BI	CHO-K1 hm4	Spontaneously immortalized cell line	Female
CVCL_H457	CHO-K1/M4/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KU93	cAMP Hunter CHO-K1 CHRM4 Gs	Spontaneously immortalized cell line	Female
CVCL_KW69	PathHunter CHO-K1 CHRM4 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LA05	PathHunter U2OS CHRM4 Total GPCR Internalization	Cancer cell line	Female
CVCL_RQ19	ValiScreen human CHRM4	Spontaneously immortalized cell line	Female
CVCL_YK38	U2OS CHRM4 PKA-Nomad	Cancer cell line	Female
CVCL_ZK78	GeneBLAzer M4-Gqo5-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.