CHRNA4

Summary

CHRNA4 (cholinergic receptor nicotinic alpha 4 subunit, HGNC:1958) is a protein-coding gene on chromosome 20q13.33, encoding Neuronal acetylcholine receptor subunit alpha-4 (P43681). Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate syna….

This gene encodes a nicotinic acetylcholine receptor, which belongs to a superfamily of ligand-gated ion channels that play a role in fast signal transmission at synapses. These pentameric receptors can bind acetylcholine, which causes an extensive change in conformation that leads to the opening of an ion-conducting channel across the plasma membrane. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene that provide protection against nicotine addiction have been described. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1137 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial sleep-related hypermotor epilepsy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 15
• Clinical variants (ClinVar): 1,181 total — 15 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 64 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000744

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1958
Approved symbol	CHRNA4
Name	cholinergic receptor nicotinic alpha 4 subunit
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	BFNC
Ensembl gene	ENSG00000101204
Ensembl biotype	protein_coding
OMIM	118504
Entrez	1137

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 11 protein_coding_CDS_not_defined, 5 retained_intron, 2 protein_coding, 2 nonsense_mediated_decay

ENST00000370263, ENST00000463705, ENST00000467563, ENST00000475033, ENST00000480012, ENST00000498043, ENST00000626188, ENST00000627000, ENST00000627869, ENST00000628606, ENST00000628665, ENST00000630240, ENST00000631289, ENST00000636481, ENST00000636652, ENST00000636726, ENST00000637243, ENST00000637443, ENST00000637628, ENST00000675470

RefSeq mRNA: 2 — MANE Select: NM_000744 NM_000744, NM_001256573

CCDS: CCDS13517

Canonical transcript exons

ENST00000370263 — 6 exons

Exon	Start	End
ENSE00001900127	63343223	63346863
ENSE00001922679	63361090	63361349
ENSE00002523811	63355975	63356084
ENSE00003531022	63349653	63351027
ENSE00003543876	63356371	63356415
ENSE00003692218	63359548	63359699

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 98.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9612 / max 61.4422, expressed in 178 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
188336	0.4653	122
188337	0.2938	116
188338	0.1050	59
188339	0.0878	51
188340	0.0093	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.37	gold quality
cortical plate	UBERON:0005343	90.25	gold quality
cingulate cortex	UBERON:0003027	85.90	gold quality
anterior cingulate cortex	UBERON:0009835	85.81	gold quality
right frontal lobe	UBERON:0002810	84.68	gold quality
liver	UBERON:0002107	83.88	gold quality
prefrontal cortex	UBERON:0000451	83.23	gold quality
amygdala	UBERON:0001876	82.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.90	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.77	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	80.75	gold quality
neocortex	UBERON:0001950	80.40	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	80.31	gold quality
frontal cortex	UBERON:0001870	79.77	gold quality
hypothalamus	UBERON:0001898	79.31	gold quality
ganglionic eminence	UBERON:0004023	79.22	gold quality
spinal cord	UBERON:0002240	78.65	gold quality
substantia nigra	UBERON:0002038	78.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.06	gold quality
cerebral cortex	UBERON:0000956	77.63	gold quality
midbrain	UBERON:0001891	76.54	gold quality
telencephalon	UBERON:0001893	76.18	gold quality
cerebellar hemisphere	UBERON:0002245	76.04	gold quality
cerebellar cortex	UBERON:0002129	75.85	gold quality
nucleus accumbens	UBERON:0001882	75.84	gold quality
forebrain	UBERON:0001890	75.82	gold quality
central nervous system	UBERON:0001017	75.61	gold quality
brain	UBERON:0000955	75.52	gold quality
cerebellum	UBERON:0002037	74.87	gold quality
caudate nucleus	UBERON:0001873	74.77	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting CHRNA4, 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-4533	100.00	69.48	2758
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-3175	99.65	66.30	2031

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Changes in nicotinic acetylcholine receptor subunits expression in brain of patients with Down syndrome and Alzheimer’s disease. (PMID:11771745)
• How mutations in the nAChRs can cause autosomal dominant nocturnal frontal lobe epilepsy (PMID:12121305)
• Mutations of the gene encoding CHRNA4 may be linked to nocturnal frontal lobe epilepsy. (PMID:12185808)
• A significant association was found for a 5’ intron 2 single nucleotide polymorphism and severe inattention problems (PMID:12556914)
• Correlative analysis between oxidative stress and deficit of nAChR alpha4 subunit indicates that increased lipid peroxidation correlates well with the decreased level of alpha4 subunit in Alzheimer’s disease brains. (PMID:12565129)
• CHRNA4 subunit is expressed in the soma of the majority of pyramidal cells, with the most alpha 4 immunoreactivity observed in CA2-4 and entorhinal cortex and relatively less in CA1 and subicular pyramidal cell soma. (PMID:12663058)
• we examined the phenotypes in two families, from the same ethnic and geographic backgrounds, with ADNFLE as a result of mutations in these two different subunits of CHRN. (PMID:12681012)
• significant decrease of the alpha4 and the alpha7 nicotinic acetylcholine receptor subunit in cortices of Parkinson patients which turns out to be similar to recent findings in Alzheimer patients. (PMID:12781587)
• the alpha4 subunit of human alpha4beta2 nicotinic receptors is phosphorylated in situ by PKA and PKC. (PMID:12782394)
• This study demonstrated an association between the CHRNA4 gene and FCs. Individuals with the T allele had a higher incidence of FCs. These data suggest that the CHRNA4 gene or a closely linked gene might be one of the susceptibility factors for FCs. (PMID:12887442)
• Evidence for S284L mutation of the CHRNA4 in a white family with autosomal dominant nocturnal frontal lobe epilepsy. (PMID:12887446)
• Reduced gene expression of the alpha4beta2 nicotinic receptor in the cerebral cortex is a major feature of the neurochemical pathology of autism, whilst post-transcriptional abnormalities of both this and the alpha7 subtype are apparent in the cerebellum (PMID:15046869)
• A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men (PMID:15154117)
• Authors’ findings provide convincing evidence for the involvement of CHRNA4 in nicotine addiction. (PMID:15790597)
• An association has been detected between the CfoI restriction fragment length polymorphism of the CHRNA4 receptor and alcoholism in Korean patients. (PMID:15902904)
• nicotinic modulation of thalamo-cortical circuitry as a key component in the control of conscious awareness in dementia with Lewy bodies (PMID:16023355)
• M1 domains on both alpha4 and beta2 play an important role for efficient expression of extracellular domain alpha4beta2 nAChRs that are high fidelity structural models of full-length alpha4beta2 nAChR (PMID:16174636)
• nicotine-induced up-regulation of alpha4beta2 acetylcholine receptors resulted primarily from an increase in assembly from large pools of unassembled subunits, but up-regulation also resulted from a 5-fold increase in the lifetime in the surface membrane (PMID:16183856)
• In Alzheimer’s disease, CHRNA4 polymorphisms and the extent of dementia seem to affect the levels of DNA oxidative damage as well as to activate factors that participate in the DNA degradation and its repair. (PMID:16332175)
• analysis of single channel conductance within the large cytoplasmic loop of 5-hydroxytryptamine type 3 and alpha4beta2 nicotinic acetylcholine receptors (PMID:16407231)
• Our present study provided the first line of direct evidence suggesting that the CHRNA4 gene combined with CHRNB2 receptor gene may be linked to schizophrenia. (PMID:16636791)
• These findings demonstrate that human nAChR beta2 or beta4 subunits can combine with alpha4 subunits to generate two forms of alpha4*-nAChR with distinctive physiological and pharmacological features. (PMID:16825297)
• The interaction was stronger in the middle-aged than in the older participants. There was a trend for individuals with combined APOE-epsilon4/CHRNA4 TT genotypes to show both lower white matter volume and slower overall RT on the attention task. (PMID:16869227)
• Analysis of six SNPs in the CHRNA4 gene provided modest support for an association with past 6 month use of alcohol in Caucasians (three SNPs with P < 0.08), but no evidence for an association with tobacco and CHRNA4 was detected. (PMID:17226798)
• This study demonstrates that the CHRNA4 gene may be one of the susceptibility factors for idiopathic generalized epilepsy. (PMID:17385675)
• We found no significant difference in RNFL thickness at the optic disc in the different genotype carriers of the APOE and CHRNA4 genes, and thereby no evidence for increased loss of ganglion cells in the retina as an effect of these genes (PMID:17488453)
• Based on our results and others, CHRNA4 may be involved in ADHD; however, its role in ADHD symptomatology remains to be clarified. (PMID:17504247)
• The auditory N1 component amplitude was higher for T allele homozygotes than for C allele carriers in CHRNA4. The visual P1 component revealed the same pattern of significant polymorphic modulation. (PMID:17590520)
• first evidence that attentional network function may be modulated by genetic variations within CHRNA4 exon 5. (PMID:17613539)
• Results of analyses ranging from basic biological approaches to clinical outcome data provide consistent evidence that 2 single-nucleotide polymorphisms in CHRNA4 are functional at a biological level and are associated with nicotine dependence phenotypes (PMID:17768273)
• did not demonstrate a significant association between methylphenidate treatment response and the polymorphisms DRD4 VNTR, CHRNA4 (rs1044396 and rs6090384) and the long (L(A) and L(G)) and short (S) forms of the serotonin transporter promoter region (PMID:17948872)
• Up-regulation of [(3)H]epibatidine binding in HEK293 cells stably expressing alpha4beta2-nAChR is significantly enhanced by co-application of tumor necrosis factor alpha. (PMID:17977823)
• discussion of the role of variability in the genes that encode the two major brain-expressed alpha subunits, alpha4 and alpha7, in modulating behavior, physiology and disease risk in both humans and mice [review] (PMID:17981562)
• subjects with the alpha4-Ser248Phe mutation mutation were shorter & had a greater body mass index than healthy volunteers & unaffected members of the pedigree; findings suggest a role of the nACh receptor in human growth regulation (PMID:18042647)
• results do not demonstrate a significant genetic difference in 7 markers from the CHRNA4 and CHRNB2 genes between schizophrenia patients who smoke and those who do not (PMID:18043764)
• Agonist-induced hump current production in heterologously expressed alpha4beta2-nicotinic acetylcholine receptors is reported. (PMID:18298895)
• This study found it affects nicotine dependence through interactions with CHRNA4 and NTRK2. (PMID:18534558)
• Visinin-like protein 1 (VILIP-1) and its interaction partner nicotinic acetylcholine receptor alpha4beta2 show partial co-localization in hippocampal interneurons. (PMID:18691652)
• CHRNA4 and CHRNB2 do not play a major role in Japanese schizophrenia. (PMID:18762859)
• CHRNA4 C/C homozygotes showed the best memory performance and greatest benefit of visuospatial attention on memory when the two systems interacted and working memory was manipulated by attention. (PMID:19016604)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	chrna4b	ENSDARG00000070724
danio_rerio	chrna4a	ENSDARG00000087071
mus_musculus	Chrna4	ENSMUSG00000027577
rattus_norvegicus	Chrna4	ENSRNOG00000011202

Paralogs (45): GABRA3 (ENSG00000011677), GABRA1 (ENSG00000022355), CHRNA3 (ENSG00000080644), GABRP (ENSG00000094755), GLRA2 (ENSG00000101958), GABRE (ENSG00000102287), CHRNE (ENSG00000108556), GABRA4 (ENSG00000109158), GLRB (ENSG00000109738), GABRR2 (ENSG00000111886), GABRG2 (ENSG00000113327), CHRNB4 (ENSG00000117971), CHRNA2 (ENSG00000120903), CHRNA10 (ENSG00000129749), CHRND (ENSG00000135902), CHRNA1 (ENSG00000138435), GLRA3 (ENSG00000145451), GABRA6 (ENSG00000145863), GABRB2 (ENSG00000145864), GLRA1 (ENSG00000145888), GABRR1 (ENSG00000146276), CHRNB3 (ENSG00000147432), CHRNA6 (ENSG00000147434), HTR3B (ENSG00000149305), GABRA2 (ENSG00000151834), CHRNB2 (ENSG00000160716), GABRG1 (ENSG00000163285), GABRB1 (ENSG00000163288), GABRB3 (ENSG00000166206), CHRFAM7A (ENSG00000166664), HTR3A (ENSG00000166736), CHRNA5 (ENSG00000169684), CHRNB1 (ENSG00000170175), CHRNA9 (ENSG00000174343), CHRNA7 (ENSG00000175344), HTR3C (ENSG00000178084), GABRG3 (ENSG00000182256), GABRR3 (ENSG00000183185), HTR3E (ENSG00000186038), HTR3D (ENSG00000186090)

Protein

Protein identifiers

Neuronal acetylcholine receptor subunit alpha-4 — P43681 (reviewed: P43681)

All UniProt accessions (4): P43681, A0A0D9SFU6, A0A6Q8PG41, H0YBH1

UniProt curated annotations — full annotation on UniProt →

Function. Component of neuronal acetylcholine receptors (nAChRs) that function as pentameric, ligand-gated cation channels with high calcium permeability among other activities. nAChRs are excitatory neurotrasnmitter receptors formed by a collection of nAChR subunits known to mediate synaptic transmission in the nervous system and the neuromuscular junction. Each nAchR subunit confers differential attributes to channel properties, including activation, deactivation and desensitization kinetics, pH sensitivity, cation permeability, and binding to allosteric modulators. CHRNA4 forms heteropentameric neuronal acetylcholine receptors with CHRNB2 and CHRNB4, as well as CHRNA5 and CHRNB3 as accesory subunits. Is the most abundant nAChR subtype expressed in the central nervous system. Found in two major stoichiometric forms,(CHRNA4)3:(CHRNB2)2 and (CHRNA4)2:(CHRNB2)3, the two stoichiometric forms differ in their unitary conductance, calcium permeability, ACh sensitivity and potentiation by divalent cation. Involved in the modulation of calcium-dependent signaling pathways, influences the release of neurotransmitters, including dopamine, glutamate and GABA.

Subunit / interactions. Neuronal AChR is composed of two different types of subunits: alpha and beta. CHRNA4 forms heteropentameric neuronal acetylcholine receptors with CHRNB2 and CHRNB4, as well as CHRNA5 and CHRNB3 as accesory subunits. Found in two major stoichiometric forms, LS (low agonist sensitivity): (CHRNA4)3:(CHRNB2)2 and HS (high agonist sensitivity): (CHRNA4)2:(CHRNB2)3, the two stoichiometric forms differ in their unitary conductance, calcium permeability, ACh sensitivity and potentiation by divalent cation. Cells produce predominantly an (CHRNA4)3:(CHRNB2)2 nAChR. The (CHRNA4)2:(CHRNB2)3 expression is selectively up-regulated by nicotine and has lower single channel conductance and calcium permeability. In the striatum, also forms CHRNA4:CHRNA6:CHRNB2 complexes. Also found in the stoichiometric form: (CHRNA4:CHRNB2)2:CHRNB3. Interacts with RIC3; which is required for proper folding and assembly. Interacts with LYPD6.

Subcellular location. Synaptic cell membrane. Cell membrane.

Disease relevance. Epilepsy, nocturnal frontal lobe, 1 (ENFL1) [MIM:600513] An autosomal dominant focal epilepsy characterized by nocturnal seizures with hyperkinetic automatisms and poorly organized stereotyped movements. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by a myriad of ligands such as acetylcholine, cytisine, nicotine, choline and epibatidine. Channel potentiation by calcium is stoichiometry-selective, CHRNA4:CHRNB2 nACh receptor is achieved by calcium association with topographically distinct sites framed by anionic residues within the CHRNA4 subunit and between the CHRNA4 and CHRNB2 subunits. nAChR activity is inhibited by the antagonist alpha-conotoxins BuIA, PnIA, GID and MII, small disulfide-constrained peptides from cone snails.

Similarity. Belongs to the ligand-gated ion channel (TC 1.A.9) family. Acetylcholine receptor (TC 1.A.9.1) subfamily. Alpha-4/CHRNA4 sub-subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P43681-1	1	yes
P43681-2	2

RefSeq proteins (2): NP_000735, NP_001243502 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002394	Nicotinic_acetylcholine_rcpt	Family
IPR006029	Neurotrans-gated_channel_TM	Domain
IPR006201	Neur_channel	Family
IPR006202	Neur_chan_lig-bd	Domain
IPR018000	Neurotransmitter_ion_chnl_CS	Conserved_site
IPR036719	Neuro-gated_channel_TM_sf	Homologous_superfamily
IPR036734	Neur_chan_lig-bd_sf	Homologous_superfamily
IPR038050	Neuro_actylchol_rec	Homologous_superfamily

Pfam: PF02931, PF02932

Catalyzed reactions (Rhea), 3 shown:

• K(+)(in) = K(+)(out) (RHEA:29463)
• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)
• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (65 total): strand 13, helix 11, mutagenesis site 6, turn 5, sequence variant 4, transmembrane region 4, modified residue 3, glycosylation site 3, compositionally biased region 2, binding site 2, topological domain 2, disulfide bond 2, splice variant 2, region of interest 2, signal peptide 1, chain 1, lipid moiety-binding region 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
8ST4	ELECTRON MICROSCOPY	2.35
8ST0	ELECTRON MICROSCOPY	2.4
8SSZ	ELECTRON MICROSCOPY	2.64
8ST3	ELECTRON MICROSCOPY	2.93
8ST2	ELECTRON MICROSCOPY	2.94
8ST1	ELECTRON MICROSCOPY	3.41
6CNJ	ELECTRON MICROSCOPY	3.7
6UR8	ELECTRON MICROSCOPY	3.71
6USF	ELECTRON MICROSCOPY	3.87
6CNK	ELECTRON MICROSCOPY	3.9
5KXI	X-RAY DIFFRACTION	3.94
2LLY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43681-F1	73.42	0.43

Antibody-complex structures (SAbDab): 9 — 6CNJ, 6CNK, 6USF, 8SSZ, 8ST0, 8ST1, 8ST2, 8ST3, 8ST4

Functional residue map

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

Ligand- & substrate-binding residues (2): 76; 78

Post-translational modifications (4): 424, 538, 541, 271

Disulfide bonds (2): 161–175, 225–226

Glycosylation sites (3): 57, 107, 174

Mutagenesis-validated functional residues (6):

Position	Phenotype
75	loss of chrna4:chrnb2 channel opening potentiation by divalent cations.
78	loss of chrna4:chrnb2 channel opening potentiation by divalent cations.
205	loss of chrna4:chrnb2 channel opening potentiation by divalent cations.
208	loss of chrna4:chrnb2 channel opening potentiation by divalent cations.
224	loss of chrna4:chrnb2 channel opening potentiation by divalent cations.
294	loss of ca(2+) permeability.

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-629587	Highly sodium permeable postsynaptic acetylcholine nicotinic receptors
R-HSA-629594	Highly calcium permeable postsynaptic nicotinic acetylcholine receptors
R-HSA-629597	Highly calcium permeable nicotinic acetylcholine receptors
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-181431	Acetylcholine binding and downstream events
R-HSA-622323	Presynaptic nicotinic acetylcholine receptors
R-HSA-622327	Postsynaptic nicotinic acetylcholine receptors

MSigDB gene sets: 245 (showing top): GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MODULE_328, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_B_CELL_ACTIVATION, GOBP_ADULT_BEHAVIOR, MODULE_64, GOBP_SYNAPTIC_TRANSMISSION_CHOLINERGIC, GOCC_CELL_SURFACE, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_HYDROXY_COMPOUND_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_PAIN

GO Biological Process (26): action potential (GO:0001508), response to hypoxia (GO:0001666), DNA repair (GO:0006281), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), response to oxidative stress (GO:0006979), signal transduction (GO:0007165), chemical synaptic transmission (GO:0007268), synaptic transmission, cholinergic (GO:0007271), neuromuscular synaptic transmission (GO:0007274), regulation of dopamine secretion (GO:0014059), sensory perception of pain (GO:0019233), monoatomic ion transmembrane transport (GO:0034220), response to nicotine (GO:0035094), behavioral response to nicotine (GO:0035095), B cell activation (GO:0042113), regulation of membrane potential (GO:0042391), nervous system process (GO:0050877), cognition (GO:0050890), membrane depolarization (GO:0051899), inhibitory postsynaptic potential (GO:0060080), acetylcholine receptor signaling pathway (GO:0095500), presynaptic modulation of chemical synaptic transmission (GO:0099171), chromatin remodeling (GO:0006338), regulation of postsynaptic membrane potential (GO:0060078), excitatory postsynaptic potential (GO:0060079)

GO Molecular Function (9): ligand-gated monoatomic ion channel activity (GO:0015276), acetylcholine receptor activity (GO:0015464), acetylcholine-gated monoatomic cation-selective channel activity (GO:0022848), acetylcholine binding (GO:0042166), ATP-dependent chromatin remodeler activity (GO:0140658), transmembrane signaling receptor activity (GO:0004888), monoatomic ion channel activity (GO:0005216), extracellular ligand-gated monoatomic ion channel activity (GO:0005230), protein binding (GO:0005515)

GO Cellular Component (13): plasma membrane (GO:0005886), acetylcholine-gated channel complex (GO:0005892), external side of plasma membrane (GO:0009897), membrane (GO:0016020), dendrite (GO:0030425), cation channel complex (GO:0034703), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), neuronal cell body (GO:0043025), synapse (GO:0045202), postsynaptic membrane (GO:0045211), neurotransmitter receptor complex (GO:0098878), synaptic membrane (GO:0097060)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Presynaptic nicotinic acetylcholine receptors	2
Postsynaptic nicotinic acetylcholine receptors	2
Acetylcholine binding and downstream events	2
Transmission across Chemical Synapses	1
Neuronal System	1
Neurotransmitter receptors and postsynaptic signal transmission	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of membrane potential	2
response to stress	2
chemical synaptic transmission	2
postsynaptic neurotransmitter receptor activity	2
monoatomic ion channel complex	2
plasma membrane signaling receptor complex	2
synaptic membrane	2
response to decreased oxygen levels	1
DNA metabolic process	1
DNA damage response	1
transport	1
metal ion transport	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
anterograde trans-synaptic signaling	1
dopamine secretion	1
regulation of catecholamine secretion	1
sensory perception	1
monoatomic ion transport	1
transmembrane transport	1
response to chemical	1
adult behavior	1
response to nicotine	1
lymphocyte activation	1
monoatomic ion transmembrane transport	1
regulation of biological quality	1
system process	1
nervous system process	1
monoatomic ion channel activity	1
ligand-gated channel activity	1
transmembrane signaling receptor activity	1
synaptic transmission, cholinergic	1
acetylcholine binding	1
excitatory extracellular ligand-gated monoatomic ion channel activity	1
ligand-gated monoatomic cation channel activity	1
transmitter-gated monoatomic ion channel activity involved in regulation of postsynaptic membrane potential	1
cation binding	1

Protein interactions and networks

STRING

1798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CHRNA4	KCNQ2	O43526	899
CHRNA4	IGBP1	P78318	809
CHRNA4	RIC3	Q7Z5B4	751
CHRNA4	KCNQ3	O43525	734
CHRNA4	DRD4	P21917	723
CHRNA4	CHRNA5	P30532	695
CHRNA4	SLC6A4	P31645	687
CHRNA4	CHRNB2	P17787	683
CHRNA4	GABBR2	O75899	681
CHRNA4	DRD1	P21728	679
CHRNA4	HTR1B	P28222	646
CHRNA4	KCNT1	Q5JUK3	638
CHRNA4	DEGS2	Q6QHC5	633
CHRNA4	CHRM5	P08912	633
CHRNA4	HTR2A	P28223	629

IntAct

36 interactions, top by confidence:

A	B	Type	Score
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
CHRNA4	SORL1	psi-mi:“MI:0915”(physical association)	0.560
EIF2S2	CHRNA4	psi-mi:“MI:0915”(physical association)	0.560
CHRNA4	CBX1	psi-mi:“MI:0915”(physical association)	0.560
CHRNA4	LRP1B	psi-mi:“MI:0915”(physical association)	0.560
CHRNA4	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
APP	CHRNA4	psi-mi:“MI:0915”(physical association)	0.560
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
CHRNA4	CRELD2	psi-mi:“MI:0915”(physical association)	0.510
CHRNA4	CHRNB2	psi-mi:“MI:0915”(physical association)	0.400
PSCA	CHRNA4	psi-mi:“MI:0915”(physical association)	0.400
CHRNA4	CSNK2B	psi-mi:“MI:0915”(physical association)	0.370
LYPD6	CHRNB2	psi-mi:“MI:0914”(association)	0.350

BioGRID (155): CHRNA4 (Reconstituted Complex), CHRNA4 (Affinity Capture-Western), CHRNB2 (Affinity Capture-Western), P2RX2 (Affinity Capture-Western), ILDR2 (Affinity Capture-MS), GOSR2 (Affinity Capture-MS), PTPRK (Affinity Capture-MS), ADCY6 (Affinity Capture-MS), ERMP1 (Affinity Capture-MS), SLC9A8 (Affinity Capture-MS), ZDHHC9 (Affinity Capture-MS), COA1 (Affinity Capture-MS), SIDT2 (Affinity Capture-MS), FAM189B (Affinity Capture-MS), NETO2 (Affinity Capture-MS)

ESM2 similar proteins: A8XNX8, O70174, P04755, P04757, P09478, P09480, P09481, P09482, P09483, P12389, P12390, P12391, P12392, P13908, P17644, P18257, P18845, P20420, P25162, P26152, P30532, P30926, P32297, P43143, P43681, P45963, P48181, P48182, P49581, P54245, Q07263, Q15822, Q15825, Q19AE6, Q27218, Q2MKA5, Q5IS51, Q5IS52, Q5IS76, Q5IS77

Diamond homologs: A8WQK3, O16926, O70174, P02708, P02709, P02710, P02711, P02712, P02713, P02716, P02717, P04755, P04756, P04757, P04758, P04759, P05377, P09478, P09479, P09480, P09481, P09482, P09483, P09484, P09628, P09690, P11230, P12389, P12390, P12391, P12392, P13908, P17644, P17787, P18257, P18845, P19370, P20420, P22456, P22770

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CHRNA4	“form complex”	“Neuronal nicotinic acetylcholine receptor complex, 3xalpha4-2xbeta2”	binding
CHRNA4	“form complex”	“Neuronal nicotinic acetylcholine receptor complex, alpha4-alpha5-beta2”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1181 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	9
Uncertain significance	476
Likely benign	409
Benign	99

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1069868	NC_000020.10:g.(?61977556)(62039909_?)del	Pathogenic
1069869	NC_000020.10:g.(?61977556)(62078210_?)del	Pathogenic
1457920	NC_000020.10:g.(?61987307)(62329916_?)del	Pathogenic
1458699	NC_000020.10:g.(?61978090)(62055579_?)del	Pathogenic
17498	NM_000744.7(CHRNA4):c.839C>T (p.Ser280Phe)	Pathogenic
17500	NM_000744.7(CHRNA4):c.851C>T (p.Ser284Leu)	Pathogenic
2427472	NC_000020.10:g.(?61978090)(62076207_?)del	Pathogenic
2427484	NC_000020.10:g.(?61978090)(62324656_?)del	Pathogenic
2427487	NC_000020.10:g.(?61978090)(62039909_?)del	Pathogenic
253462	GRCh37/hg19 20q13.33(chr20:61977731-62105264)x1	Pathogenic
3248244	NC_000020.10:g.(?61978090)(62062742_?)del	Pathogenic
41030	NM_000744.7(CHRNA4):c.867GCT[3] (p.Leu291dup)	Pathogenic
476031	NC_000020.10:g.(?61977556)(62159505_?)del	Pathogenic
831044	NC_000020.10:g.(?61977556)(62129136_?)del	Pathogenic
832463	NC_000020.10:g.(?61977556)(62103836_?)del	Pathogenic
1202676	NM_000744.7(CHRNA4):c.823A>T (p.Ile275Phe)	Likely pathogenic
1326331	GRCh37/hg19 20q13.33(chr20:61974574-62129187)	Likely pathogenic
1326332	GRCh37/hg19 20q13.33(chr20:61974574-62078190)	Likely pathogenic
1326333	GRCh37/hg19 20q13.33(chr20:61986847-62055559)	Likely pathogenic
1326337	GRCh37/hg19 20q13.33(chr20:61986847-62224435)	Likely pathogenic
1802235	NM_000744.7(CHRNA4):c.1113_1114insTATG (p.Ile372fs)	Likely pathogenic
205014	NM_000744.7(CHRNA4):c.544T>C (p.Trp182Arg)	Likely pathogenic
3391126	NM_000744.7(CHRNA4):c.481T>C (p.Cys161Arg)	Likely pathogenic
3707646	NM_000744.7(CHRNA4):c.938C>A (p.Thr313Asn)	Likely pathogenic

SpliceAI

1510 predictions. Top by Δscore:

Variant	Effect	Δscore
20:63346736:T:TA	donor_gain	1.0000
20:63351023:CAGCA:C	acceptor_gain	1.0000
20:63351026:CA:C	acceptor_gain	1.0000
20:63351028:C:CC	acceptor_gain	1.0000
20:63355973:A:AC	donor_gain	1.0000
20:63355974:C:CC	donor_gain	1.0000
20:63356367:TCA:T	donor_loss	1.0000
20:63356370:C:CT	donor_loss	1.0000
20:63356414:TCCT:T	acceptor_loss	1.0000
20:63356425:C:CT	acceptor_gain	1.0000
20:63356426:G:T	acceptor_gain	1.0000
20:63359546:A:AC	donor_gain	1.0000
20:63359547:C:A	donor_loss	1.0000
20:63359547:C:CC	donor_gain	1.0000
20:63359547:CCA:C	donor_gain	1.0000
20:63359696:CTGG:C	acceptor_gain	1.0000
20:63359700:C:CC	acceptor_gain	1.0000
20:63361089:CCGCG:C	donor_gain	1.0000
20:63349646:GACTT:G	donor_loss	0.9900
20:63349647:ACTTA:A	donor_loss	0.9900
20:63349648:CTTAC:C	donor_loss	0.9900
20:63349649:TTA:T	donor_loss	0.9900
20:63349650:TACC:T	donor_loss	0.9900
20:63349652:C:A	donor_loss	0.9900
20:63351025:GCA:G	acceptor_gain	0.9900
20:63351025:GCAC:G	acceptor_loss	0.9900
20:63351026:CAC:C	acceptor_gain	0.9900
20:63351026:CACT:C	acceptor_loss	0.9900
20:63351027:ACTGG:A	acceptor_loss	0.9900
20:63351028:C:A	acceptor_loss	0.9900

AlphaMissense

4067 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:63346823:C:G	R600P	1.000
20:63350784:C:A	W209C	1.000
20:63350784:C:G	W209C	1.000
20:63350786:A:G	W209R	1.000
20:63350786:A:T	W209R	1.000
20:63350929:C:T	C161Y	1.000
20:63346826:T:A	D599V	0.999
20:63346826:T:G	D599A	0.999
20:63346849:C:A	W591C	0.999
20:63346849:C:G	W591C	0.999
20:63346851:A:G	W591R	0.999
20:63346851:A:T	W591R	0.999
20:63350482:A:G	L310P	0.999
20:63350547:G:C	F288L	0.999
20:63350547:G:T	F288L	0.999
20:63350549:A:G	F288L	0.999
20:63350557:A:G	L285P	0.999
20:63350581:A:G	L277P	0.999
20:63350616:G:C	F265L	0.999
20:63350616:G:T	F265L	0.999
20:63350618:A:G	F265L	0.999
20:63350662:A:G	L250P	0.999
20:63350886:G:C	C175W	0.999
20:63350887:C:G	C175S	0.999
20:63350887:C:T	C175Y	0.999
20:63350888:A:G	C175R	0.999
20:63350888:A:T	C175S	0.999
20:63350905:G:T	P169H	0.999
20:63350906:G:A	P169S	0.999
20:63350908:A:C	F168C	0.999

dbSNP variants (sampled 300 via entrez): RS1000245569 (20:63346972 C>T), RS1000858319 (20:63354090 C>A,T), RS1000890863 (20:63353311 C>G,T), RS1000933963 (20:63348478 C>T), RS1001019053 (20:63359837 C>T), RS1001207661 (20:63349468 C>A,G), RS1001472660 (20:63346270 C>G,T), RS1001674299 (20:63361797 G>A), RS1001775859 (20:63354972 T>C), RS1002023032 (20:63348075 C>T), RS1002082478 (20:63353276 C>T), RS1002146945 (20:63355147 C>G), RS1002167853 (20:63359421 C>G,T), RS1002256719 (20:63345397 CAT>C), RS1002403571 (20:63357279 T>C,G)

Disease associations

OMIM: gene MIM:118504 | disease phenotypes: MIM:600513, MIM:188890, MIM:121200, MIM:613720, MIM:615369, MIM:615190, MIM:616373, MIM:616409

GenCC curated gene-disease

Disease	Classification	Inheritance
familial sleep-related hypermotor epilepsy	Definitive	Autosomal dominant
autosomal dominant nocturnal frontal lobe epilepsy 1	Definitive	Autosomal dominant
autosomal dominant nocturnal frontal lobe epilepsy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
familial sleep-related hypermotor epilepsy	Definitive	AD

Mondo (14): familial sleep-related hypermotor epilepsy (MONDO:0000030), developmental and epileptic encephalopathy (MONDO:0100620), autosomal dominant nocturnal frontal lobe epilepsy 1 (MONDO:0010899), tobacco addiction, susceptibility to (MONDO:0100460), seizures, benign familial neonatal, 1 (MONDO:0007365), developmental and epileptic encephalopathy, 7 (MONDO:0013387), developmental and epileptic encephalopathy 94 (MONDO:0014150), dyskeratosis congenita, autosomal recessive 5 (MONDO:0014076), pulmonary fibrosis and/or bone marrow failure, Telomere-related, 3 (MONDO:0014613), developmental and epileptic encephalopathy, 33 (MONDO:0014625), amyotrophic lateral sclerosis (MONDO:0004976), intellectual disability (MONDO:0001071), frontotemporal dementia (MONDO:0017276), (MONDO:0020300)

Orphanet (10): Sleep-related hypermotor epilepsy (Orphanet:98784), Self-limited neonatal epilepsy (Orphanet:1949), KCNQ2-related developmental and epileptic encephalopathy (Orphanet:439218), Epilepsy with myoclonic-atonic seizures (Orphanet:1942), Lennox-Gastaut syndrome (Orphanet:2382), Idiopathic pulmonary fibrosis (Orphanet:2032), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Amyotrophic lateral sclerosis (Orphanet:803), Frontotemporal dementia (Orphanet:282), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

27 total (28 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000020	Urinary incontinence
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000733	Motor stereotypy
HP:0000739	Anxiety
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001345	Psychotic mentation
HP:0002069	Bilateral tonic-clonic seizure
HP:0002268	Paroxysmal dystonia
HP:0002883	Hyperventilation
HP:0003829	Typified by incomplete penetrance
HP:0004305	Involuntary movements
HP:0007018	Attention deficit hyperactivity disorder
HP:0007359	Focal-onset seizure
HP:0011174	Focal hyperkinetic seizure
HP:0011182	Interictal epileptiform activity
HP:0011193	EEG with focal spikes
HP:0011463	Childhood onset
HP:0025235	NREM parasomnia
HP:0025236	Sleep walking
HP:0031535	Increased theta frequency activity in EEG
HP:0031589	Suicidal ideation
HP:0031951	Nocturnal seizures
HP:0100543	Cognitive impairment
HP:0007354	Amyotrophic lateral sclerosis

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000359_1	Chronic obstructive pulmonary disease	1.000000e-10
GCST002945_25	Emphysema imaging phenotypes	2.000000e-07
GCST002945_3	Emphysema imaging phenotypes	5.000000e-07
GCST003185_1	Nicotine dependence	8.000000e-09
GCST006697_28	Parental longevity (combined parental attained age, Martingale residuals)	4.000000e-07
GCST006701_5	Parental longevity (father’s attained age)	2.000000e-08
GCST007602_4	Smoking behaviour (cigarettes smoked per day)	9.000000e-07
GCST008496_2	Nicotine dependence	8.000000e-07
GCST008496_3	Nicotine dependence	3.000000e-07
GCST008496_4	Nicotine dependence	2.000000e-06
GCST008667_8	Smoking status (heavy vs never)	1.000000e-07
GCST008803_17	Smoking behaviour (cigarette pack-years)	2.000000e-16
GCST008809_11	Smoking behaviour (cigarettes smoked per day)	7.000000e-10
GCST011702_13	Smoking cessation	2.000000e-21
GCST011754_7	Nicotine dependence	4.000000e-16

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0007626	emphysema imaging measurement
EFO:0007796	parental longevity
EFO:0006525	cigarettes per day measurement
EFO:0006527	smoking status measurement
EFO:0009115	tobacco smoke exposure measurement
EFO:0004319	smoking cessation

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D057180	Frontotemporal Dementia	C10.228.140.380.266.299; C10.574.950.300.299; C18.452.845.800.300.299; F03.615.400.380.299
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C579932	Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (supp.)
C567743	Epilepsy, Benign Neonatal, 1, And-Or Myokymia (supp.)
C563930	Epilepsy, Nocturnal Frontal Lobe, Type 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (6): CHEMBL1882 (SINGLE PROTEIN), CHEMBL1907589 (PROTEIN COMPLEX), CHEMBL1907591 (PROTEIN COMPLEX), CHEMBL3038461 (PROTEIN COMPLEX), CHEMBL4524133 (PROTEIN COMPLEX GROUP), CHEMBL4804182 (PROTEIN COMPLEX GROUP)

Molecules with ChEMBL bioactivity

64 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 657,596 (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
CHEMBL1076903	VARENICLINE	4	5,807
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1179047	CHLOROPROCAINE	4	52,577
CHEMBL1186610	ANISOTROPINE	4	473
CHEMBL1189679	PALONOSETRON	4	9,399
CHEMBL1201269	CHLORPHENTERMINE	4	3,921
CHEMBL1201303	PYRVINIUM	4	1,797
CHEMBL1201340	DIPHEMANIL	4	9
CHEMBL12713	SERTINDOLE	4	8,984
CHEMBL1360	ATRACURIUM	4	22
CHEMBL1401	NITAZOXANIDE	4	9,504
CHEMBL14376	ILOPERIDONE	4	7,878
CHEMBL159226	MOXISYLYTE	4	1,514
CHEMBL1617	RIFAXIMIN	4	13,380
CHEMBL178	DAUNORUBICIN	4	203,756
CHEMBL189963	PALBOCICLIB	4	13,102
CHEMBL2107011	OXYPERTINE	4	173,804
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL28333	MEDAZEPAM	4	6,650
CHEMBL374478	RIFAMPIN	4	93,834
CHEMBL37744	ZIMELDINE	4
CHEMBL479	THIORIDAZINE	4
CHEMBL535	SUNITINIB	4
CHEMBL56337	EPALRESTAT	4
CHEMBL56367	NIMESULIDE	4
CHEMBL56564	TROPISETRON	4
CHEMBL596	FENTANYL	4
CHEMBL601719	CRIZOTINIB	4
CHEMBL639	AZELASTINE	4
CHEMBL667	ACETYLCHOLINE	4

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

PharmGKB clinical annotations

12 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1044394	Toxicity	3	ethanol	Alcohol abuse
rs1044396	Other	3	nicotine	Tobacco Use Disorder
rs1044396	Efficacy	3	varenicline	Tobacco Use Disorder
rs1044396	Toxicity	3	nicotine
rs1044397	Other	3	nicotine	Tobacco Use Disorder
rs2229959	Other	3	nicotine	Tobacco Use Disorder
rs2229959	Toxicity	3	nicotine
rs2236196	Other	3	nicotine	Tobacco Use Disorder
rs3787138	Toxicity	3	nicotine	Tobacco Use Disorder
rs3787140	Toxicity	3	nicotine	Tobacco Use Disorder
rs6090378	Toxicity	3	nicotine	Tobacco Use Disorder

PharmGKB variants

12 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1044396	CHRNA4	3	5.50	3	nicotine;varenicline
rs1044397	CHRNA4	3	2.75	1	nicotine
rs2229959	CHRNA4	3	2.50	2	nicotine
rs2236196	CHRNA4	3	2.00	2	nicotine
rs2273504	CHRNA4		0.00	0
rs6090384	CHRNA4		0.00	0
rs1044394	CHRNA4	3	0.00	1	ethanol
rs2273502	CHRNA4		0.00	0
rs6090378	CHRNA4	3	0.00	1	nicotine
rs3787138	CHRNA4	3	0.00	1	nicotine
rs3787140	CHRNA4	3	0.00	1	nicotine
rs3827020	CHRNA4		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — Nicotinic acetylcholine receptors (nACh)

Most potent curated ligand interactions (13 total), top 13:

Ligand	Action	Affinity	Parameter
[125I]epibatidine	Full agonist	11.0	pKd
[3H]epibatidine	Full agonist	11.0	pKd
tebanicline	Partial agonist	10.43	pKi
varenicline	Agonist	10.4	pKi
[3H]cytisine	Full agonist	10.0	pKd
[3H]nicotine	Full agonist	9.4	pKd
SUVN-911	Antagonist	8.82	pKi
nicotine	Agonist	8.66	pKi
lobeline	Agonist	8.3	pKi
atracurium	Antagonist	8.1	pIC50
rivanicline	Agonist	7.6	pKi
mecamylamine	Channel blocker	5.44	pIC50
hexamethonium	Channel blocker	4.04	pIC50

Binding affinities (BindingDB)

173 measured of 209 human assays (259 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(S)-2-(6-Chloro-pyridin-3-yl)-7-aza-bicyclo[2.2.1]heptane	KI	0.05 nM
syn-7-(6-chloro-pyridin-3-yl)-2-azabicyclo[2.2.1]heptane	KI	0.0785 nM
5-[5-(azetidin-2-ylmethoxy)-6-methyl-3-pyridinyl]pent-4-yn-1-ol	KI	0.087 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
3-(4-Methyl-isoxazol-5-ylmethyl)-1-aza-bicyclo[2.2.1]heptane	KI	0.3 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
CHEMBL4740159	KI	0.32 nM
6-(6-Chloro-pyridin-3-yl)-8-aza-bicyclo[3.2.1]octane	KI	0.343 nM
VARENICLINE	KI	0.48 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
7-(3-methylisoxazol-5-yl)-6-aza-bicyclo[2.2.1]heptane	KI	0.763 nM
11-Bromo-1,2,3,4,5,6-hexahydro-1,5-methano-pyrido[1,2-a][1,5]diazocin-8-one	EC50	1.1 nM
CHEMBL3329537	KI	1.1 nM
CHEMBL4791046	KI	1.3 nM
CHEMBL2179534	KI	1.5 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
3,7-diazabicyclo[3.3.1]nonan-3-yl-(4,5-dibromofuran-2-yl)methanone	KI	1.6 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL4793576	KI	1.6 nM
(1S,4S)-2-(6-fluoro-3-pyridinyl)-2,5-diazabicyclo[2.2.1]-heptane	EC50	1.62 nM
CHEMBL2179547	KI	1.7 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL2177548	KI	1.7 nM
CHEMBL3329538	KI	1.7 nM
CHEMBL2179531	KI	2.4 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
4-[[(2-oxo-1-piperidin-3-yl-4-pyridinyl)methylamino]methyl]-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one	KI	3.5 nM	US-11667638: 4-substitued cytisine analogues
CHEMBL2177550	KI	4.4 nM
CHEMBL2179540	KI	4.6 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl-(4,5-dibromofuran-2-yl)methanone	KI	4.9 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
(4-bromo-5-methylfuran-2-yl)-(3,7-diazabicyclo[3.3.1]nonan-3-yl)methanone	KI	5.2 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL2179544	KI	5.2 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
6-[5-(azetidin-2-ylmethoxy)-6-methyl-3-pyridinyl]hex-5-yn-1-ol	KI	5.3 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
CHEMBL3329539	KI	5.4 nM
CHEMBL3329542	KI	7 nM
CHEMBL2179543	KI	7.3 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
6-(6-Chloro-pyridin-3-yl)-8-aza-bicyclo[3.2.1]octan-3-ol	KI	7.4 nM
(+/-)-exo-(1R,2R,4R)-2-(6-chloropyridin-3-yl)-7-aza-bicyclo[2.2.1]heptane	KI	7.6 nM
3-(azetidin-2-ylmethoxy)-5-(6-chlorohex-1-ynyl)-2-methylpyridine	KI	8.6 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
3,7-diazabicyclo[3.3.1]nonan-3-yl-(5-isocyanofuran-2-yl)methanone	KI	8.7 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
3-(azetidin-2-ylmethoxy)-5-(6-fluorohex-1-ynyl)-2-methylpyridine	KI	8.7 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
CHEMBL2179516	KI	9.2 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL2178154	KI	9.6 nM
CHEMBL2179530	KI	9.7 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL2179967	KI	9.9 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
3,7-diazabicyclo[3.3.1]nonan-3-yl(1,2-oxazol-3-yl)methanone	KI	10 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL2057714	KI	10 nM
3-(azetidin-2-ylmethoxy)-5-(2-cyclopropylethynyl)-2-methylpyridine	KI	13 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
CHEMBL2177554	KI	13 nM
1,3a,8-trimethyl-1H,2H,3H,3aH,8H,8aH-pyrrolo[2,3-b]indol-5-yl N-methylcarbamate	IC50	14 nM
2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl-(3-methyl-1,2-oxazol-4-yl)methanone	KI	14 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl-(3-isocyanofuran-2-yl)methanone	KI	14 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl-(3-fluoro-5-methylfuran-2-yl)methanone	KI	14 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
CHEMBL2179541	KI	14 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes
3-(azetidin-2-ylmethoxy)-5-hex-1-ynyl-2-methylpyridine	KI	16 nM	US-9993465: 2,5-disubstituted-pyridyl nicotinic ligands, and methods of use thereof
CHEMBL2179526	KI	16 nM	US-8921410: Nicotinic acetylcholine receptor sub-type selective amides of diazabicycloalkanes

ChEMBL bioactivities

2025 potent at pChembl≥5 of 2344 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	EPIBATIDINE
11.00	Kd	0.01	nM	EPIBATIDINE
11.00	Kd	0.0101	nM	EPIBATIDINE
10.77	Ki	0.017	nM	CHEMBL2024096
10.77	Ki	0.01698	nM	CHEMBL2024096
10.74	Ki	0.018	nM	CHEMBL245243
10.70	EC50	0.02	nM	EPIBATIDINE
10.70	Ki	0.02	nM	CHEMBL4168511
10.68	Ki	0.021	nM	CHEMBL361465
10.66	Ki	0.022	nM	CHEMBL361465
10.59	Ki	0.026	nM	(+)-EPIBATIDINE
10.57	Ki	0.027	nM	AZIDOEPIBATIDINE
10.52	Kd	0.03	nM	(-)-EPIBATIDINE
10.52	Ki	0.03	nM	CHEMBL2164666
10.51	Ki	0.031	nM	CHEMBL3086984
10.49	Ki	0.032	nM	CHEMBL3086994
10.48	Ki	0.033	nM	EPIBATIDINE
10.47	Ki	0.034	nM	TEBANICLINE
10.46	Ki	0.035	nM	EPIBATIDINE
10.44	EC50	0.036	nM	CHEMBL62858
10.42	Ki	0.038	nM	CHEMBL291498
10.40	Ki	0.04	nM	CHEMBL59986
10.40	Ki	0.04	nM	VARENICLINE
10.40	Ki	0.04	nM	CHEMBL63102
10.37	Ki	0.043	nM	CHEMBL3086985
10.35	Ki	0.045	nM	(+)-EPIBATIDINE
10.35	Ki	0.045	nM	NICOTINE
10.34	Ki	0.046	nM	CHEMBL3086982
10.34	Ki	0.046	nM	EPIBATIDINE
10.31	Ki	0.049	nM	CHEMBL3086991
10.30	Ki	0.05	nM	EPIBATIDINE
10.30	Ki	0.05	nM	CHEMBL3086995
10.30	EC50	0.05	nM	CHEMBL305106
10.30	Ki	0.05	nM	CHEMBL59986
10.30	Ki	0.05	nM	CHEMBL54902
10.28	Ki	0.052	nM	CHEMBL59986
10.26	Ki	0.055	nM	TEBANICLINE
10.25	Ki	0.0558	nM	EPIBATIDINE
10.22	EC50	0.06	nM	VARENICLINE
10.22	Ki	0.06	nM	VARENICLINE
10.22	Ki	0.06	nM	EPIBATIDINE
10.21	Ki	0.062	nM	CHEMBL2024096
10.15	Ki	0.07	nM	EPIBATIDINE
10.14	Ki	0.072	nM	CHEMBL3086993
10.14	Ki	0.073	nM	CHEMBL185061
10.14	Ki	0.072	nM	EPIBATIDINE
10.12	Ki	0.076	nM	CHEMBL3086986
10.11	Ki	0.0785	nM	CHEMBL220476
10.10	Ki	0.08	nM	CHEMBL2164664
10.09	Ki	0.082	nM	CHEMBL2164664

PubChem BioAssay actives

1781 with measured affinity, of 5534 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
2-(6-chloro-3-pyridinyl)-7-methyl-7-azabicyclo[2.2.1]heptane	304128: Displacement of [3H]epibatidine from alpha-4-beta-2 nAChR	ki	<0.0001	uM
2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane	1410535: Displacement of [3H]epibatidine from alpha4beta2 nAChR (unknown origin) expressed in HEK cell membranes after 4 hrs by liquid scintillation counting method	ki	<0.0001	uM
(1R,4R)-2-pyridin-3-yl-2,5-diazabicyclo[2.2.1]heptane	1359521: Agonist activity at alpha4beta2 nAChR (unknown origin)	ki	<0.0001	uM
(1S,2S,4R)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane	1252856: Binding affinity to alpha4beta2 nAChR (unknown origin)	ki	<0.0001	uM
5-[[(2R)-azetidin-2-yl]methoxy]-2-chloropyridine	146301: Compound was evaluated for its ability to displace [3H]cytisine from K177 cells expressing human Nicotinic acetylcholine receptor alpha4-beta2	ki	<0.0001	uM
2-(5-azido-6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane	146309: Binding affinity to alpha4 beta-2 receptor subtype from mouse fibroblast M10 cells was measured using [3 H]nicotine	ki	<0.0001	uM
2-(6-chloro-3-pyridinyl)-9-azabicyclo[4.2.1]non-2-ene	640183: Displacement of [3H]epibatidine from nAChR alpha4beta2 receptor	ki	<0.0001	uM
Varenicline	1647833: Displacement of [3H]cytisine from human alpha4beta2 nAChR expressed in CHOK1 cell membrane by microbeta scintillation counting method	ki	<0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]pyridine	146301: Compound was evaluated for its ability to displace [3H]cytisine from K177 cells expressing human Nicotinic acetylcholine receptor alpha4-beta2	ki	<0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-(2-phenylethynyl)pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	<0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(3-fluorophenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	<0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(3-fluoro-5-methylphenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	<0.0001	uM
3-[2-[5-[[(2S)-azetidin-2-yl]methoxy]-3-pyridinyl]ethynyl]-5-fluoro-N,N-dimethylaniline	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	<0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(3-methylphenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	<0.0001	uM
(1R,2R,4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane	1275134: Binding affinity to alpha4beta2 nACh receptor (unknown origin) expressed in Xenopus oocytes	kd	<0.0001	uM
Nicotine	1359521: Agonist activity at alpha4beta2 nAChR (unknown origin)	ki	<0.0001	uM
5-iodo-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one	246575: Change in membrane potential in K-177 cells expressing acetylcholine central neuronal receptor alpha4-beta2 subunits	ec50	<0.0001	uM
2-(6-chloro-3-pyridinyl)-2,5-diazabicyclo[2.2.1]heptane	1359521: Agonist activity at alpha4beta2 nAChR (unknown origin)	ki	<0.0001	uM
1-decyl-3-[(2S)-1-methylpyrrolidin-2-yl]pyridin-1-ium iodide	1243907: Binding affinity to alpha4beta2 nAChR (unknown origin)	ki	0.0001	uM
6-methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),5,9-tetraene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
1-dodecyl-3-[(2S)-1-methylpyrrolidin-2-yl]pyridin-1-ium iodide	1243907: Binding affinity to alpha4beta2 nAChR (unknown origin)	ki	0.0001	uM
6-[5-[[(2S)-azetidin-2-yl]methoxy]-3-pyridinyl]hex-5-yn-1-ol	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
(1S,2S,5R)-2-(pyridin-3-yloxymethyl)-3-azabicyclo[3.1.0]hexane;hydrochloride	1647833: Displacement of [3H]cytisine from human alpha4beta2 nAChR expressed in CHOK1 cell membrane by microbeta scintillation counting method	ki	0.0001	uM
(1S,4S)-2-pyridin-3-yl-2,5-diazabicyclo[2.2.1]heptane	1359521: Agonist activity at alpha4beta2 nAChR (unknown origin)	ki	0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-phenylpyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
(4S)-2-(6-chloro-3-pyridinyl)-7-azabicyclo[2.2.1]heptane	146639: Binding affinity towards nicotinic acetylcholine receptor alpha4-beta2	ki	0.0001	uM
6-(6-chloro-3-pyridinyl)-8-azabicyclo[3.2.1]octane	276249: Displacement of [3H]epibatidine from human recombinant alpha4beta2 nAChR in HEK293 cells by SPA assay	ki	0.0001	uM
7-(6-chloro-3-pyridinyl)-2-azabicyclo[2.2.1]heptane	276249: Displacement of [3H]epibatidine from human recombinant alpha4beta2 nAChR in HEK293 cells by SPA assay	ki	0.0001	uM
(1R,5S)-7-pyridin-3-yl-3-azabicyclo[3.3.1]non-6-ene	705817: Displacement of [3H]nicotine from human alpha4beta2 nAChR expressed in human SH-EP1 cells	ki	0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(3-fluoro-5-methoxyphenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(3-chlorophenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(4-fluorophenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(3,5-difluorophenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
3-[[(2S)-azetidin-2-yl]methoxy]-5-[2-(2-fluorophenyl)ethynyl]pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
3-[[(2R)-azetidin-2-yl]methoxy]-5-(2-phenylethynyl)pyridine	1053303: Displacement of [3H]epibatidine from human alpha4beta2 nAChR after 4 hrs by cell-based assay	ki	0.0001	uM
6-methyl-5-oxa-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),6,9-tetraene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
7-methyl-5-oxa-6,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,6,8-tetraene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
5-bromo-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one	246575: Change in membrane potential in K-177 cells expressing acetylcholine central neuronal receptor alpha4-beta2 subunits	ec50	0.0001	uM
5-chloro-7,11-diazatricyclo[7.3.1.02,7]trideca-2,4-dien-6-one	246575: Change in membrane potential in K-177 cells expressing acetylcholine central neuronal receptor alpha4-beta2 subunits	ec50	0.0001	uM
4,5-dichloro-10-azatricyclo[6.3.1.02,7]dodeca-2,4,6-triene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
6-methyl-5-thia-7,13-diazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),6,9-tetraene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),5,9-tetraene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
3-pyridin-3-yl-3,7-diazabicyclo[3.3.1]nonane	705817: Displacement of [3H]nicotine from human alpha4beta2 nAChR expressed in human SH-EP1 cells	ki	0.0001	uM
7-phenyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2,4(8),5,9-tetraene	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0001	uM
1-(10-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-4-yl)ethanone	254476: Binding affinity for human Nicotinic acetylcholine receptor alpha4-beta2 expressed in HEK 293 cells using [3H]nicotine	ki	0.0002	uM
5-(6-chloro-3-pyridinyl)-2-azabicyclo[2.2.1]heptane	276249: Displacement of [3H]epibatidine from human recombinant alpha4beta2 nAChR in HEK293 cells by SPA assay	ki	0.0002	uM
cytisinicline	239394: Binding affinity against nicotinic acetylcholine receptor alpha4-beta2 in human HEK293 cells using [3H]- nicotine as radioligand	ki	0.0002	uM
(1R,3S,5R)-3-[(5-chloro-3-pyridinyl)oxymethyl]-2-azabicyclo[3.1.0]hexane;hydrochloride	1647833: Displacement of [3H]cytisine from human alpha4beta2 nAChR expressed in CHOK1 cell membrane by microbeta scintillation counting method	ki	0.0002	uM
(1S,2S,5R)-2-[(5-chloro-3-pyridinyl)oxymethyl]-3-azabicyclo[3.1.0]hexane;hydrochloride	1647833: Displacement of [3H]cytisine from human alpha4beta2 nAChR expressed in CHOK1 cell membrane by microbeta scintillation counting method	ki	0.0002	uM
(1S,2S,5R)-2-[(6-chloro-3-pyridinyl)oxymethyl]-3-azabicyclo[3.1.0]hexane	1647833: Displacement of [3H]cytisine from human alpha4beta2 nAChR expressed in CHOK1 cell membrane by microbeta scintillation counting method	ki	0.0002	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetylcholine	decreases activity, affects binding, increases activity, decreases reaction, affects cotreatment (+3 more)	16
Nicotine	increases response to substance, decreases activity, decreases reaction, increases phosphorylation, increases activity (+2 more)	8
cytisine	increases activity, decreases reaction, affects binding	4
Varenicline	affects binding, increases activity	4
epibatidine	affects binding, decreases reaction, increases activity	3
Mecamylamine	increases activity, affects binding, decreases activity, decreases reaction	3
Tubocurarine	affects activity, affects binding, decreases reaction, increases activity, increases reaction (+1 more)	3
tetrabromobisphenol A	affects cotreatment, affects binding, decreases reaction, increases activity	2
imidacloprid	affects binding, decreases reaction, increases activity	2
Resveratrol	increases expression, affects cotreatment, decreases expression	2
Dihydro-beta-Erythroidine	affects binding, decreases activity, decreases reaction, increases activity	2
Dimethylphenylpiperazinium Iodide	affects binding, decreases reaction, increases activity	2
Ethinyl Estradiol	affects cotreatment, increases activity, affects activity, increases reaction, decreases reaction (+1 more)	2
Flame Retardants	affects cotreatment, affects binding, decreases reaction, increases activity	2
Lobeline	decreases activity, decreases reaction, increases phosphorylation, affects binding	2
Pancuronium	decreases activity, affects binding, decreases reaction, increases activity	2
Physostigmine	affects binding, decreases activity, decreases reaction, affects activity, increases reaction	2
Vecuronium Bromide	affects binding, decreases reaction, increases activity, decreases activity	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects cotreatment, decreases reaction, increases activity	1
bisphenol A	decreases reaction, affects activity, affects binding	1
subecholine	increases activity, affects binding, decreases reaction, decreases activity	1
decabromobiphenyl ether	affects cotreatment, decreases reaction, increases activity	1
ethyl-p-hydroxybenzoate	decreases expression	1
diethyl maleate	increases expression	1
sodium arsenite	increases expression	1
decamethonium	decreases reaction, affects binding, decreases activity	1
2,4,2’,4’-tetrachlorobiphenyl	affects binding, decreases reaction, increases activity, affects cotreatment	1
antimony trioxide	affects cotreatment, decreases reaction, increases activity	1
4-nonylphenol	affects binding, decreases reaction, affects activity	1

ChEMBL screening assays

624 unique, capped per target: 497 binding, 125 functional, 1 toxicity, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1212436	Functional	Antagonist activity at human alpha4 nAChR in human IMR32 cells	Identification of novel alpha7 nAChR positive allosteric modulators with the use of pharmacophore in silico screening methods. — Bioorg Med Chem Lett
CHEMBL3376389	Binding	Inhibition of alpha4 nAChR (unknown origin)	Identification, optimization, and pharmacology of acylurea GHS-R1a inverse agonists. — J Med Chem
CHEMBL5166939	Toxicity	Inhibition of human recombinant nAChRalpha4/beta2 incubated for 120 mins by radiometric scintillation counting method	Design of a Potent, Selective, and Brain-Penetrant Inhibitor of Wnt-Deactivating Enzyme Notum by Optimization of a Crystallographic Fragment Hit. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_5I63	K177	Transformed cell line	Female
CVCL_D1KG	PrecisION hnAChR alpha4/alpha6/beta2-HEK	Transformed cell line	Female
CVCL_D1KH	PrecisION hnAChR alpha4/beta2-HEK	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03779672	PHASE4	COMPLETED	Memantine for Epileptic Encephalopathy
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
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