HTR6

Summary

HTR6 (5-hydroxytryptamine receptor 6, HGNC:5301) is a protein-coding gene on chromosome 1p36.13, encoding 5-hydroxytryptamine receptor 6 (P50406). G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen.

This gene encodes a protein that belongs to the seven-transmembrane G protein-coupled receptor family of proteins. The encoded protein couples with the Gs alpha subunit and stimulates adenylate cyclase to activate the cyclic AMP-dependent signaling pathway. This receptor is thought to regulate cholinergic neuronal transmission in the brain. Several antidepressants and antipsychotic drugs have a high affinity for this receptor.

Source: NCBI Gene 3362 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 87 total
• Druggable target: yes — 127 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000871

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5301
Approved symbol	HTR6
Name	5-hydroxytryptamine receptor 6
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	5-HT6, 5-HT6R
Ensembl gene	ENSG00000158748
Ensembl biotype	protein_coding
OMIM	601109
Entrez	3362

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000289753

RefSeq mRNA: 1 — MANE Select: NM_000871 NM_000871

CCDS: CCDS197

Canonical transcript exons

ENST00000289753 — 3 exons

Exon	Start	End
ENSE00001040777	19678567	19678725
ENSE00001040779	19664875	19666467
ENSE00001263964	19678919	19680966

Expression profiles

Bgee: expression breadth broad, 74 present calls, max score 92.14.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7289 / max 99.0468, expressed in 158 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1081	0.6397	146
1080	0.0717	37
1082	0.0175	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	92.14	silver quality
olfactory bulb	UBERON:0002264	91.82	silver quality
Brodmann (1909) area 10	UBERON:0013541	89.36	silver quality
diaphragm	UBERON:0001103	87.14	silver quality
pancreatic ductal cell	CL:0002079	82.46	silver quality
tongue squamous epithelium	UBERON:0006919	81.56	silver quality
epithelial cell of pancreas	CL:0000083	81.27	silver quality
male germ cell	CL:0000015	80.88	silver quality
frontal pole	UBERON:0002795	79.85	silver quality
mucosa of urinary bladder	UBERON:0001259	79.79	silver quality
sperm	CL:0000019	79.57	silver quality
paraflocculus	UBERON:0005351	79.54	gold quality
vena cava	UBERON:0004087	79.51	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	79.48	silver quality
middle frontal gyrus	UBERON:0002702	78.73	silver quality
lateral globus pallidus	UBERON:0002476	78.26	silver quality
vastus lateralis	UBERON:0001379	77.63	gold quality
quadriceps femoris	UBERON:0001377	77.07	gold quality
body of tongue	UBERON:0011876	77.02	silver quality
pericardium	UBERON:0002407	76.85	silver quality
inferior vagus X ganglion	UBERON:0005363	76.59	silver quality
Brodmann (1909) area 46	UBERON:0006483	76.52	silver quality
cardia of stomach	UBERON:0001162	76.31	silver quality
endometrium epithelium	UBERON:0004811	76.07	gold quality
substantia nigra pars compacta	UBERON:0001965	75.96	silver quality
ventral tegmental area	UBERON:0002691	75.93	silver quality
triceps brachii	UBERON:0001509	75.75	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.69	silver quality
trachea	UBERON:0003126	75.60	gold quality
pons	UBERON:0000988	75.17	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.47

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

57 targeting HTR6, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-8485	100.00	77.57	4731
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-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-513C-5P	99.50	68.42	1730
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-1207-5P	99.49	69.11	2983

Literature-anchored findings (GeneRIF, showing 32)

• 5-HT6 receptor gene polymorphism C267T is associated with Parkinson’s disease. (PMID:11889255)
• Association of the 5-hydroxytryptamine(6) receptor gene in Alzheimer’s disease. apolipoprotein E epsilon 4 status. the 267C allele of the 5-HT(6) receptor gene may not be a genetic risk factor for AD. (PMID:12023056)
• significant relationship between 5-HT(6) receptor gene polymorphism (C267T) and self-transcendence (PMID:14698468)
• These data do not support the idea that the 5-HT(6) receptor gene plays a major role in the etiopathogenesis of schizophrenia. (PMID:15048641)
• The human cloned 5-HT6 receptor is stably transfected in HeLa cells. (PMID:15482912)
• The serotonin type 6 (5-HT(6)) receptor is a G-protein coupled receptor (GPCR) coupled to a stimulatory G-protein (G(S)). (PMID:15737640)
• In aging control patients, the 5-HT6 receptor was expressed by pyramidal cells and some stellate cells,in layers II-V, and layer I, where a distinct label was observed in neurons and surrounding fibers.In AD patients was significantly decreased by 40%. (PMID:16640790)
• evaluation of association of 7 serotonin signal transduction-linked SNP’s [HTR1A (rs6295), HTR2A (rs6313, rs6311 & rs7997012), HTR6 (rs1805054), TPH1 (rs1800532) & TPH2 (rs1386494)] with major depressive disorder; no association found (PMID:19590397)
• SNP might have a role in the etiology of suicide in male subjects in the Portuguese population. (PMID:19782122)
• Jab1 provides a novel signal transduction pathway for 5-HT(6)R and may play an important role in 5-HT(6)R-mediated behavior changes in the brain (PMID:20093369)
• Data show that analogues of 5-cyclic amine-3-arylsulfonylindazoles have been identified as high-affinity 5-HT(6) receptor ligands. (PMID:20170099)
• we found no association involving HTR6 polymorphism and mood disorder in the Japanese population (PMID:20394784)
• detected association between 2 markers (rs6693503 and rs1805054) and three markers (rs6693503, rs1805054 and rs4912138) in HTR6 and METH-induced psychosis respectively. HTR6 may play important role in pathophysiology of METH-induced psychosis in Japanese (PMID:20705401)
• Common variants in the gene for HT6R do not contribute to obesity. (PMID:21273698)
• [review] Since discovery of the 5-HT6 receptor and development of its small-molecule ligands, neurochemical and localization studies have clearly demonstrated its central role in modulating GABAergic neurotransmission across brain structures and networks. (PMID:21329782)
• There was a statistically significant difference in semantic memory scores among the three genotype groups of T267C in 5-HT6. (PMID:21728060)
• present findings showed the presence of a higher density of 5-HT(6) receptors, as labeled by [(125)I]SB-258585, in striatum than in hippocampus and prefrontal cortex, and specifically within the neuronal body (PMID:22278721)
• results indicate that tagging SNPs in HTR6 may not play a role in the pathophysiology of schizophrenia. (PMID:22745941)
• When expressed in pyramidal neuron progenitors, serotonin receptor 5-HT6 transgene decreases the migration speed of cortical pyramidal neurons, thereby affecting a fundamental step in the assembly of neural circuits. (PMID:22833193)
• These observations suggest that recruitment of mTOR by prefrontal 5-HT(6) receptors contributes to the perturbed cognition in schizophrenia, offering new vistas for its therapeutic control. (PMID:23027611)
• Data indicate that hydrogen-bond formation of a methoxy or hydroxy group is not important for binding at the 5-HT6 receptor. (PMID:23542166)
• [review] Controlling the activity of 5-HTR6 receptors seems to provide benefits by alleviating cognitive impairments. (PMID:23844689)
• Studies indicate that serotonin 5-HT6 receptor (5-HT6R) has been proposed as a promising drug target for cognition enhancement in Alzheimer’s disease (AD). (PMID:24850589)
• that HTR6 plays an important role in modulating seizure activity and that the blockade of the 5-HT6 receptor/mTOR pathway could be a potential therapeutic target for epilepsy treatment (PMID:25034463)
• Serotonin 6 receptor has a role in Alzheimer’s disease and depression (PMID:26449188)
• Correlation of 5-HTR6 gene polymorphism with vestibular migraine. (PMID:31587366)
• Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer’s Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P. (PMID:32417774)
• Constitutive Activity of Serotonin Receptor 6 Regulates Human Cerebral Organoids Formation and Depression-like Behaviors. (PMID:33357407)
• HTR6 and SSTR3 ciliary targeting relies on both IC3 loops and C-terminal tails. (PMID:33372037)
• [5-HT6 receptor-mTOR: An hyperactive couple in neuropathic pain].", trans “Recepteur 5-HT6 et mTOR - Un couple hyperactif dans la douleur neuropathique. (PMID:34003104)
• Systematic Analysis of Neurotransmitter Receptors in Human Breast Cancer Reveals a Strong Association With Outcome and Uncovers HTR6 as a Survival-Associated Gene Potentially Regulating the Immune Microenvironment. (PMID:35359970)
• Peripheral 5-HT/HTR6 axis is responsible for obesity-associated hypertension. (PMID:38086448)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	htr6	ENSDARG00000016095
mus_musculus	Htr6	ENSMUSG00000028747
drosophila_melanogaster	5-HT7	FBGN0004573

Paralogs (8): HTR2A (ENSG00000102468), HTR1B (ENSG00000135312), HTR2B (ENSG00000135914), HTR2C (ENSG00000147246), HTR7 (ENSG00000148680), HTR5A (ENSG00000157219), HTR1E (ENSG00000168830), HTR1F (ENSG00000179097)

Protein

Protein identifiers

5-hydroxytryptamine receptor 6 — P50406 (reviewed: P50406)

Alternative names: Serotonin receptor 6

All UniProt accessions (1): P50406

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled receptor for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone and a mitogen. Also has a high affinity for tricyclic psychotropic drugs. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors. HTR6 is coupled to G(s) G alpha proteins and mediates activation of adenylate cyclase activity. Controls pyramidal neurons migration during corticogenesis, through the regulation of CDK5 activity. Is an activator of mTOR signaling.

Subunit / interactions. Interacts with MTOR, RPTOR and NF1. Interacts with CDK5.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in several human brain regions, most prominently in the caudate nucleus.

Domain organisation. Specificity for G(s) G alpha proteins is determined by the length of transmembrane regions 5 and 6 (TM5 and TM6).

Similarity. Belongs to the G-protein coupled receptor 1 family.

RefSeq proteins (1): NP_000862* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR002232	5HT6_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (53 total): helix 15, mutagenesis site 10, topological domain 8, transmembrane region 7, turn 3, compositionally biased region 2, binding site 2, strand 2, chain 1, region of interest 1, disulfide bond 1, sequence conflict 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7YS6	ELECTRON MICROSCOPY	3
8JLZ	ELECTRON MICROSCOPY	3.09
7XTB	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50406-F1	73.23	0.38

Antibody-complex structures (SAbDab): 3 — 7XTB, 7YS6, 8JLZ

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): 106; 288

Disulfide bonds (1): 99–180

Mutagenesis-validated functional residues (10):

Position	Phenotype
106	abolished g-protein coupled receptor activity in response to serotonin.
110	decreased g-protein coupled receptor activity in response to serotonin.
111	decreased g-protein coupled receptor activity in response to serotonin.
182	decreased g-protein coupled receptor activity in response to serotonin.
188	decreased g-protein coupled receptor activity in response to serotonin.
192	abolished g-protein coupled receptor activity in response to serotonin.
281	abolished g-protein coupled receptor activity in response to serotonin.
284	abolished g-protein coupled receptor activity in response to serotonin.
285	decreased g-protein coupled receptor activity in response to serotonin.
310	decreased g-protein coupled receptor activity in response to serotonin.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-390666	Serotonin receptors
R-HSA-418555	G alpha (s) 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: 100 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOMF_G_PROTEIN_COUPLED_SEROTONIN_RECEPTOR_ACTIVITY, BENPORATH_ES_WITH_H3K27ME3, MODULE_274, MODULE_45, MODULE_64, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, GOBP_FOREBRAIN_CELL_MIGRATION, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, KEGG_NEUROACTIVE_LIGAND_RECEPTOR_INTERACTION

GO Biological Process (11): G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating serotonin receptor signaling pathway (GO:0007192), chemical synaptic transmission (GO:0007268), cerebral cortex cell migration (GO:0021795), positive regulation of TOR signaling (GO:0032008), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), positive regulation of cell communication (GO:0010647), positive regulation of signaling (GO:0023056), G protein-coupled serotonin receptor signaling pathway (GO:0098664)

GO Molecular Function (6): histamine receptor activity (GO:0004969), G protein-coupled serotonin receptor activity (GO:0004993), neurotransmitter receptor activity (GO:0030594), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515), serotonin receptor activity (GO:0099589)

GO Cellular Component (5): plasma membrane (GO:0005886), cilium (GO:0005929), dendrite (GO:0030425), synapse (GO:0045202), 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	4
cell communication	2
signaling	2
G protein-coupled amine receptor activity	2
transmembrane signaling receptor activity	2
adenylate cyclase activity	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
serotonin receptor signaling pathway	1
anterograde trans-synaptic signaling	1
cerebral cortex development	1
telencephalon cell migration	1
TOR signaling	1
regulation of TOR signaling	1
positive regulation of intracellular signal transduction	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
regulation of cell communication	1
positive regulation of cellular process	1
regulation of signaling	1
positive regulation of biological process	1
G protein-coupled serotonin receptor activity	1
histamine binding	1
serotonin binding	1
G protein-coupled serotonin receptor signaling pathway	1
signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
neuron projection	1
dendritic tree	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

492 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTR6	HTR3A	P46098	596
HTR6	FYN	P06241	552
HTR6	SLC6A4	P31645	465
HTR6	IFT88	Q13099	431
HTR6	ADCY3	O60266	424
HTR6	ARL13B	Q3SXY8	384
HTR6	CDK5	Q00535	381
HTR6	VCP	P55072	355
HTR6	NAV1	Q8NEY1	354
HTR6	SMO	Q99835	351
HTR6	INMT	O95050	349
HTR6	CD1A	P06126	348
HTR6	TULP3	O75386	340
HTR6	CEP135	Q66GS9	326
HTR6	HTR3B	O95264	326
HTR6	HTR2A	P28223	326

IntAct

59 interactions, top by confidence:

A	B	Type	Score
FYN	HTR6	psi-mi:“MI:0915”(physical association)	0.630
HTR6	FYN	psi-mi:“MI:0915”(physical association)	0.630
HTR6	FYN	psi-mi:“MI:0407”(direct interaction)	0.630
NOVA1	HTR6	psi-mi:“MI:0915”(physical association)	0.600
NOVA1	HTR6	psi-mi:“MI:0403”(colocalization)	0.600
HTR6	MAP1B	psi-mi:“MI:0915”(physical association)	0.580
HTR6		psi-mi:“MI:0915”(physical association)	0.400
Nova1	HTR6	psi-mi:“MI:0915”(physical association)	0.400
	HTR6	psi-mi:“MI:0915”(physical association)	0.400
HTR6	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	HTR6	psi-mi:“MI:0915”(physical association)	0.400
HTR6	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
HTR6	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	HTR6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (69): ATM (Affinity Capture-MS), ATR (Affinity Capture-MS), ATXN10 (Affinity Capture-MS), CAND2 (Affinity Capture-MS), CDK5 (Affinity Capture-MS), CLTC (Affinity Capture-MS), NCAPG (Affinity Capture-MS), COG3 (Affinity Capture-MS), COPG2 (Affinity Capture-MS), DNM2 (Affinity Capture-MS), EXOC2 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), TTI1 (Affinity Capture-MS), MTOR (Affinity Capture-MS), NCDN (Affinity Capture-MS)

ESM2 similar proteins: A0A6I8PUB9, O00155, O00270, O08726, O14842, O43603, O60755, O88626, O88634, O88853, O88854, P0C5I1, P13945, P46092, P50406, Q15722, Q28524, Q3T181, Q3ZC80, Q5IS65, Q60483, Q6XKD3, Q76JU8, Q76JU9, Q76JV1, Q80UC6, Q862A8, Q862A9, Q8HYC3, Q8K3T4, Q8MJV2, Q8MJV3, Q8TDU6, Q8TDU9, Q920E0, Q924U0, Q95252, Q969F8, Q96G91, Q96P69

Diamond homologs: A0A678XMK4, O02662, O02666, O14804, O19091, O42574, O70528, O77680, O77700, P07700, P11617, P17124, P18089, P21728, P23944, P25021, P25100, P25102, P25115, P28221, P28565, P35405, P35406, P42289, P42290, P42291, P43141, P46626, P47747, P47800, P49145, P50406, P53452, P53454, P60021, P61752, P79400, P97288, P97292, P97714

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
HTR6	“up-regulates activity”	GNAS	binding
HTR6	“up-regulates activity”	GNAL	binding
HTR6	“up-regulates activity”	GNAI1	binding
HTR6	“up-regulates activity”	GNAO1	binding
HTR6	“up-regulates activity”	GNAZ	binding
HTR6	“up-regulates activity”	GNAQ	binding
HTR6	“up-regulates activity”	GNA14	binding
HTR6	“up-regulates activity”	GNA13	binding
serotonin(1+)	“up-regulates activity”	HTR6	“chemical activation”
serotonin	“up-regulates activity”	HTR6	“chemical activation”
CDK5	“down-regulates activity”	HTR6	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	72
Likely benign	8
Benign	6

Top pathogenic / likely-pathogenic (0)

SpliceAI

544 predictions. Top by Δscore:

Variant	Effect	Δscore
1:19678562:C:CA	acceptor_gain	1.0000
1:19678565:A:AG	acceptor_gain	1.0000
1:19678565:AG:A	acceptor_gain	1.0000
1:19678565:AGGT:A	acceptor_gain	1.0000
1:19678566:G:GA	acceptor_gain	1.0000
1:19678566:GG:G	acceptor_gain	1.0000
1:19678566:GGT:G	acceptor_gain	1.0000
1:19678566:GGTG:G	acceptor_gain	1.0000
1:19678566:GGTGC:G	acceptor_gain	1.0000
1:19666465:CAGGT:C	donor_loss	0.9900
1:19666466:AG:A	donor_loss	0.9900
1:19666467:GGT:G	donor_loss	0.9900
1:19666468:GTAC:G	donor_loss	0.9900
1:19678727:TAATG:T	donor_loss	0.9900
1:19678918:GGCC:G	acceptor_gain	0.9900
1:19676401:G:GT	donor_gain	0.9800
1:19677141:G:GT	donor_gain	0.9800
1:19678635:G:GT	donor_gain	0.9800
1:19666418:T:TA	donor_gain	0.9700
1:19666419:G:GA	donor_gain	0.9700
1:19678561:CCGCA:C	acceptor_gain	0.9700
1:19678562:CGCAG:C	acceptor_gain	0.9700
1:19678563:GCAGG:G	acceptor_gain	0.9700
1:19678564:CAGGT:C	acceptor_gain	0.9700
1:19678565:A:G	acceptor_gain	0.9700
1:19678566:G:T	acceptor_gain	0.9700
1:19678677:C:T	donor_gain	0.9700
1:19678915:CCAG:C	acceptor_loss	0.9700
1:19678916:CAGGC:C	acceptor_loss	0.9700
1:19678917:A:AG	acceptor_gain	0.9700

AlphaMissense

2779 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:19665965:C:T	S71F	0.999
1:19665968:A:C	D72A	0.999
1:19665968:A:G	D72G	0.999
1:19665968:A:T	D72V	0.999
1:19666114:A:C	S121R	0.999
1:19666116:C:A	S121R	0.999
1:19666116:C:G	S121R	0.999
1:19678981:C:A	N312K	0.999
1:19678981:C:G	N312K	0.999
1:19678993:C:A	N316K	0.999
1:19678993:C:G	N316K	0.999
1:19665965:C:A	S71Y	0.998
1:19665969:C:A	D72E	0.998
1:19665969:C:G	D72E	0.998
1:19666029:G:C	W92C	0.998
1:19666029:G:T	W92C	0.998
1:19666101:C:A	N116K	0.998
1:19666101:C:G	N116K	0.998
1:19666364:T:A	I204K	0.998
1:19678681:T:C	F277L	0.998
1:19678683:C:A	F277L	0.998
1:19678683:C:G	F277L	0.998
1:19678693:T:A	W281R	0.998
1:19678693:T:C	W281R	0.998
1:19678982:A:C	S313R	0.998
1:19678984:C:A	S313R	0.998
1:19678984:C:G	S313R	0.998
1:19665885:C:A	N44K	0.997
1:19665885:C:G	N44K	0.997
1:19665956:T:A	L68H	0.997

dbSNP variants (sampled 300 via entrez): RS1000265157 (1:19670852 T>C), RS1000316231 (1:19671094 G>A), RS1000380701 (1:19664953 C>A,G,T), RS1000602665 (1:19672311 T>C), RS1000654851 (1:19672549 G>A,T), RS1000732304 (1:19665145 G>C), RS1000878625 (1:19665398 G>T), RS1001199112 (1:19680750 A>C), RS1001225783 (1:19671414 C>G), RS1001443289 (1:19671450 T>C), RS1001571243 (1:19665374 C>T), RS1001757624 (1:19677469 A>G), RS1001990661 (1:19666882 A>G), RS1002052098 (1:19665630 C>A,G,T), RS1002230059 (1:19670053 A>G)

Disease associations

OMIM: gene MIM:601109 | 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
GCST003453_3	Chronotype	5.000000e-08
GCST003454_1	Morning vs. evening chronotype	8.000000e-07
GCST003837_9	Chronotype	1.000000e-08
GCST003838_9	Morning vs. evening chronotype	3.000000e-06
GCST007565_50	Morning person	3.000000e-15

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2096904 (PROTEIN FAMILY), CHEMBL3371 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

127 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 404,400 (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
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1043	DAPSONE	4	64,779
CHEMBL1065	METHYSERGIDE	4	8,455
CHEMBL1112	ARIPIPRAZOLE	4	24,205
CHEMBL1113	AMOXAPINE	4	20,128
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL1172	DESLORATADINE	4	19,720
CHEMBL1200492	NEFAZODONE HYDROCHLORIDE	4	5,428
CHEMBL1200517	DIHYDROERGOTAMINE MESYLATE	4	2,704
CHEMBL1200776	CINACALCET HYDROCHLORIDE	4	1,220
CHEMBL1200809	AZELASTINE HYDROCHLORIDE	4	3,805
CHEMBL1201	THIOTHIXENE	4	13,101
CHEMBL1201203	BENZTROPINE	4	9,334
CHEMBL1201356	METHYLERGONOVINE	4	3,335
CHEMBL126224	IPRINDOLE	4	4,398
CHEMBL12713	SERTINDOLE	4	8,984
CHEMBL1289	HALOPROGIN	4	8,799
CHEMBL1336	SORAFENIB	4	86,060
CHEMBL1411979	METHAPYRILENE	4	6,036
CHEMBL1423	PIMOZIDE	4
CHEMBL14376	ILOPERIDONE	4
CHEMBL1442422	DIBENZEPIN	4
CHEMBL1491	AMLODIPINE	4
CHEMBL1508	ESCITALOPRAM	4
CHEMBL1516474	TEGASEROD MALEATE	4
CHEMBL1615374	VILAZODONE HYDROCHLORIDE	4
CHEMBL1626	CLEMASTINE	4
CHEMBL1628227	DOXEPIN	4
CHEMBL1633	KETOTIFEN FUMARATE	4

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

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1805054	HTR6	3	2.00	1	risperidone
rs9659997	HTR6		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — 5-Hydroxytryptamine receptors

Most potent curated ligand interactions (82 total), top 25:

Ligand	Action	Affinity	Parameter
[11C]GSK215083	Antagonist	9.8	pKi
intepirdine	Antagonist	9.77	pKi
methiothepin	Antagonist	9.4	pKi
idalopirdine	Antagonist	9.08	pKi
SB399885	Antagonist	9.0	pKi
[125I]SB258585	Antagonist	9.0	pKd
SB 271046	Antagonist	8.9	pKi
cerlapirdine	Antagonist	8.89	pKi
[3H]LSD	Full agonist	8.7	pKd
WAY-181187	Agonist	8.7	pKi
E6801	Partial agonist	8.7	pKi
ergotamine	Full agonist	8.6	pKi
SB258585	Antagonist	8.53	pKi
SB357134	Antagonist	8.5	pKi
bufotenine	Antagonist	8.4	pKi
Lysergide	Full agonist	8.4	pKi
Ro 63-0563	Antagonist	8.4	pKi
WAY-208466	Agonist	8.32	pKi
zotepine	Inverse agonist	8.3	pKi
dihydroergotamine	Antagonist	8.3	pKi
[3H]Ro 63-0563	Antagonist	8.3	pKd
EMD-386088	Agonist	8.13	pIC50
clozapine	Inverse agonist	8.1	pKi
lisuride	Partial agonist	8.1	pKi
ICI 169369	Antagonist	8.0	pKi

Binding affinities (BindingDB)

810 measured of 869 human assays (895 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
8-(3-chlorophenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.05 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
3-(difluoromethyl)-6-fluoro-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.066 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
3-(difluoromethyl)-5-fluoro-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.074 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
8-(1H-indol-5-ylsulfonyl)-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.083 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-chloro-3-(difluoromethyl)-1-((4-methoxy-3-(piperazin-1-yl) phenyl)sulfonyl)-1H-indole	IC50	0.085 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
3-(difluoromethyl)-6-bromo-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.09 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
6-chloro-3-(difluoromethyl)-1-((3-(4-isopropylpiperazin-1-yl)-4-methoxyphenyl)sulfonyl)-1H-indole	IC50	0.09 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
6-chloro-1-((3-(4-cyclopropylpiperazin-1-yl)-4-methoxyphenyl) sulfonyl)-3-(difluoromethyl)-1H-indole	IC50	0.092 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
8-(1-benzothiophen-3-ylsulfonyl)-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.1 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
3-(difluoromethyl)-6-chloro-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.1 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
NSC_104911	KI	0.1 nM
8-[3-(difluoromethoxy)phenyl]sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.11 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(3-chloro-5-fluorophenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.11 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(benzenesulfonyl)-6-ethoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.11 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(benzenesulfonyl)-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.12 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-chloro-8-(1H-indol-5-ylsulfonyl)-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.13 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-methoxy-8-[3-(trifluoromethyl)phenyl]sulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.13 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-chloro-3-(difluoromethyl)-1-((3-(4-ethylpiperazin-1-yl)-4-methoxyphenyl)sulfonyl)-1H-indole	IC50	0.13 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
6-chloro-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.14 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
3-(difluoromethyl)-1-((4-methoxy-3-(4-methylpiperazin-1-yl) phenyl)sulfonyl)-6-(trifluoromethyl)-1H-indole	IC50	0.14 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
8-(benzenesulfonyl)-6-chloro-1-methyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.15 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-methoxy-8-(1-methylindol-3-yl)sulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.16 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(1-benzothiophen-5-ylsulfonyl)-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.16 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-chloro-8-(1-methylindol-3-yl)sulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.17 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-methoxy-8-thiophen-2-ylsulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.17 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-bromo-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl) sulfonyl)-1H-indole	IC50	0.17 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
8-(2-fluorophenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.19 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-methoxy-8-[3-(trifluoromethoxy)phenyl]sulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.19 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-chloro-8-indol-1-ylsulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.2 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(3-fluorophenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.2 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
3-(difluoromethyl)-5-bromo-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.2 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
6-chloro-1-((4-methoxy-3-(piperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.21 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
8-(benzenesulfonyl)-6-methyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.22 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
6-methyl-8-[3-(trifluoromethyl)phenyl]sulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.22 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
5-chloro-3-(difluoromethyl)-1-((4-methoxy-3-(4-methylpiperazin-1-yl)phenyl)sulfonyl)-1H-indole	IC50	0.22 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
6-(aminomethyl)-3-(3-chlorophenyl)sulfonyl-N,5,7-trimethylpyrazolo[1,5-a]pyrimidin-2-amine	IC50	0.227 nM	US-8618114: Substituted 3-arylsulfonyl-pyrazolo[1,5-A]pyrimidines, serotonin 5-HT6 receptor antagonists and methods for the production and use thereof
8-(3,5-dichlorophenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.23 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(1-benzothiophen-5-ylsulfonyl)-6-methyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.23 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
9-(benzenesulfonyl)-7-chloro-2,3,4,5-tetrahydro-1H-[1]benzofuro[2,3-d]azepine	KI	0.25 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
3-(difluoromethyl)-1-((3-(4-ethylpiperazin-1-yl)-4-methoxyphenyl) sulfonyl)-6-(trifluoromethyl)-1H-indole	IC50	0.25 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
5-(1H-indol-5-ylsulfonyl)-9,15-dimethyl-9,15-diazatetracyclo[10.2.1.02,10.03,8]pentadeca-2(10),3(8),4,6-tetraene	KI	0.26 nM	US-8575186: Epiminocycloalkyl[b] indole derivatives as serotonin sub-type 6 (5-HT6) modulators and uses thereof
8-(1-benzothiophen-3-ylsulfonyl)-6-chloro-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.26 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
3-(difluoromethyl)-6-fluoro-1-((4-methoxy-3-(piperazin-1-yl) phenyl)sulfonyl)-1H-indole	IC50	0.26 nM	US-9663498: Aromatic heterocyclic compounds and their application in pharmaceuticals
6-methoxy-8-thiophen-3-ylsulfonyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.27 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(4-chlorophenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.28 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
8-(3-chlorophenyl)sulfonyl-6-methyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.28 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia
5-(1-benzothiophen-3-ylsulfonyl)-7,9-dimethyl-9,15-diazatetracyclo[10.2.1.02,10.03,8]pentadeca-2(10),3(8),4,6-tetraene	KI	0.29 nM	US-8575186: Epiminocycloalkyl[b] indole derivatives as serotonin sub-type 6 (5-HT6) modulators and uses thereof
E-6837	EC50	0.29 nM
3-(benzenesulfonyl)-2-N,5-dimethylpyrazolo[1,5-a]pyrimidine-2,7-diamine	IC50	0.293 nM	US-8618114: Substituted 3-arylsulfonyl-pyrazolo[1,5-A]pyrimidines, serotonin 5-HT6 receptor antagonists and methods for the production and use thereof
8-[3-(difluoromethoxy)phenyl]sulfonyl-6-methyl-1,2,3,4-tetrahydro-[1]benzofuro[3,2-c]pyridine	KI	0.3 nM	US-9067949: Benzofuro[3,2-c] pyridines and related analogs as serotonin sub-type 6 (5-HT6) modulators for the treatment of obesity, metabolic syndrome, cognition and schizophrenia

ChEMBL bioactivities

5910 potent at pChembl≥5 of 5974 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.40	Ki	0.04	nM	CHEMBL3329438
10.30	Kd	0.05012	nM	CHEMBL3785512
10.30	Ki	0.05	nM	CHEMBL3692995
10.30	Ki	0.05012	nM	CHEMBL1084794
10.20	Ki	0.0631	nM	CHEMBL398034
10.20	Ki	0.0631	nM	CHEMBL1085462
10.19	EC50	0.06457	nM	CHEMBL362628
10.18	IC50	0.066	nM	CHEMBL5894995
10.13	IC50	0.074	nM	CHEMBL6037204
10.10	Ki	0.07943	nM	CHEMBL1086326
10.08	Ki	0.083	nM	CHEMBL3692882
10.07	Ki	0.085	nM	CHEMBL5189271
10.07	IC50	0.085	nM	CHEMBL5189271
10.06	Ki	0.088	nM	CHEMBL1083654
10.05	IC50	0.09	nM	CHEMBL5810706
10.05	IC50	0.09	nM	CHEMBL6038874
10.04	IC50	0.092	nM	CHEMBL5944459
10.00	Ki	0.1	nM	CHEMBL368209
10.00	Ki	0.1	nM	CHEMBL3692990
10.00	Ki	0.1	nM	CHEMBL4852099
10.00	IC50	0.1	nM	CHEMBL5968227
10.00	Ki	0.1	nM	CHEMBL1086252
10.00	Ki	0.1	nM	CHEMBL1085120
10.00	Ki	0.1	nM	CHEMBL1086113
10.00	Ki	0.1	nM	CHEMBL1085658
9.96	Ki	0.11	nM	CHEMBL3692968
9.96	Ki	0.11	nM	CHEMBL3692993
9.96	Ki	0.11	nM	CHEMBL3696966
9.95	Ki	0.112	nM	CHEMBL1082763
9.94	Ki	0.1148	nM	CHEMBL24474
9.92	Ki	0.12	nM	CHEMBL3692867
9.90	Ki	0.1259	nM	CHEMBL363792
9.90	Ki	0.1259	nM	CHEMBL365569
9.90	Ki	0.1259	nM	CHEMBL1085037
9.90	Ki	0.1259	nM	CHEMBL1083886
9.90	Ki	0.1259	nM	CHEMBL1084711
9.89	Ki	0.13	nM	CHEMBL3692910
9.89	Ki	0.13	nM	CHEMBL3692974
9.89	IC50	0.13	nM	CHEMBL5843513
9.85	IC50	0.14	nM	CHEMBL6039781
9.85	IC50	0.14	nM	CHEMBL5808765
9.85	Ki	0.1413	nM	CHEMBL1922616
9.85	Ki	0.14	nM	CHEMBL1922616
9.82	Ki	0.15	nM	CHEMBL3692894
9.80	Ki	0.16	nM	CHEMBL2413990
9.80	Ki	0.16	nM	CHEMBL3692988
9.80	Ki	0.16	nM	CHEMBL3692989
9.80	Ki	0.1585	nM	CHEMBL394690
9.80	Ki	0.1585	nM	CHEMBL1086079
9.80	Ki	0.1585	nM	CHEMBL1086323

PubChem BioAssay actives

4056 with measured affinity, of 6100 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
1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-butylpiperidin-4-yl)propan-1-one	1712264: Displacement of [3H]-LSD from human 5-HT6 receptor expressed in HEK293 cells in presence of serotonin incubated for 60 mins	ki	<0.0001	uM
5-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]-3-methyl-1-benzothiophene-2-sulfonamide	239164: Inhibition of [3H]LSD binding to human 5-hydroxytryptamine 6 receptor expressed in HEK293 cells	ki	0.0001	uM
6-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]imidazo[2,1-b][1,3]thiazole-5-sulfonamide	369094: Agonist activity at human 5HT6 receptor expressed in HEK293F cells assessed as stimulation of cAMP level after 30 mins by HTRF assay Inhibition of rat adrenergic alpha1 receptor	ec50	0.0001	uM
4-[(2-bromo-6-piperazin-1-yl-4-pyridinyl)sulfonyl]aniline	6544: Binding constant towards serotonin receptor subtype 5-hydroxytryptamine 6 receptor expressed in HeLa cells using [3H]LSD as radioligand	ki	0.0001	uM
2-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methylamino]-1,4-dihydroimidazol-5-one	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
6-chloro-3-(difluoromethyl)-1-(4-methoxy-3-piperazin-1-ylphenyl)sulfonylindole	1863240: Displacement of [3H]-LSD from human 5HT6R expressed in CHO cell membranes incubated for 120 mins by scintillation counter method	ki	0.0001	uM
N-[2-[1-(benzenesulfonyl)indol-4-yl]oxyethyl]-N’-[(4-fluorophenyl)methyl]ethane-1,2-diamine	1784741: Displacement of [3H]-LSD from human 5HT6R expressed in CHO-K1 cell membranes incubated for 1 hr by scintillation counter method	ki	0.0001	uM
4-(2,6-dichlorophenyl)sulfonyl-8-piperazin-1-yl-2,3-dihydro-1,4-benzoxazine	307663: Displacement of [3H]LSD from human recombinant 5HT6 receptor expressed in HEK293 cells	ki	0.0001	uM
10-(benzenesulfonyl)-N-methyl-1,8,12-triazatricyclo[7.3.0.02,6]dodeca-2(6),7,9,11-tetraen-11-amine	482324: Displacement of [3H]lysergic acid diethylamide from human recombinant 5HT6 receptor expressed in human HeLa cells	ki	0.0001	uM
3-(benzenesulfonyl)-N-methyl-6,7,8,9-tetrahydropyrazolo[1,5-a]quinazolin-2-amine	482324: Displacement of [3H]lysergic acid diethylamide from human recombinant 5HT6 receptor expressed in human HeLa cells	ki	0.0001	uM
1-methoxy-4-(4-naphthalen-1-ylsulfonylphenyl)piperazine	239920: Binding affinity for human 5-hydroxytryptamine 6 receptor	ki	0.0001	uM
[(1R)-6-(1H-indol-3-ylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
2-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methylamino]acetamide	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
2-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methylamino]ethanol	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
1-[6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]-N,N-dimethylmethanamine	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
N-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]acetamide	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
N-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]-2-hydroxyacetamide	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
(1R)-6-(3-fluorophenyl)sulfonyl-1-[(sulfamoylamino)methyl]-1,2,3,4-tetrahydronaphthalene	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
1-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]azetidin-3-ol	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0001	uM
4-benzyl-8-piperazin-1-yl-1,4-benzoxazin-3-one	1178357: Antagonist activity at human recombinant 5HT6 receptor expressed in CHO cells	ki	0.0002	uM
3-(benzenesulfonyl)-8-piperazin-1-ylquinoline	1154620: Displacement of [3H]LSD from human 5-HT6 receptor expressed in human HeLa cells after 1 hr by scintillation spectroscopic analysis	ki	0.0002	uM
2-[[6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]guanidine	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
N-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]methanesulfonamide	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
1-[(3R)-6-(benzenesulfonyl)-2,3-dihydro-1,4-benzodioxin-3-yl]-N-methylmethanamine	1178357: Antagonist activity at human recombinant 5HT6 receptor expressed in CHO cells	ki	0.0002	uM
6-chloro-1-(4-methoxy-3-piperazin-1-ylphenyl)sulfonyl-3-methylindole	1863240: Displacement of [3H]-LSD from human 5HT6R expressed in CHO cell membranes incubated for 120 mins by scintillation counter method	ki	0.0002	uM
6-chloro-1-(4-methoxy-3-piperazin-1-ylphenyl)sulfonylindole	1863240: Displacement of [3H]-LSD from human 5HT6R expressed in CHO cell membranes incubated for 120 mins by scintillation counter method	ki	0.0002	uM
1-[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]-1-methylurea	1351506: Binding affinity to 5HT6R (unknown origin)	ki	0.0002	uM
3-[4-[4-[1-(benzenesulfonyl)indol-4-yl]piperazin-1-yl]butyl]-1H-indole-5-carbonitrile	2116578: Displacement of [3H]-Citalopram from human SERT extracted from HEK293 cell membrane assessed as inhibition constant incubated for 60 mins by microbeta2 scintillation counter analysis	ki	0.0002	uM
4-(2-fluorophenyl)sulfonyl-6-methoxy-8-piperazin-1-yl-2,3-dihydro-1,4-benzoxazine	307663: Displacement of [3H]LSD from human recombinant 5HT6 receptor expressed in HEK293 cells	ki	0.0002	uM
N-[3-(2-aminoethyl)-1H-indol-5-yl]-5-chloronaphthalene-2-sulfonamide	239920: Binding affinity for human 5-hydroxytryptamine 6 receptor	ki	0.0002	uM
3-(3-chlorophenyl)sulfonyl-N,5,7-trimethylpyrazolo[1,5-a]pyrimidin-2-amine	568359: Antagonist activity at human recombinant 5HT6 receptor expressed in HEK293 cells assessed as inhibition of serotonin-induced cAMP accumulation after 2 hrs	ki	0.0002	uM
10-(benzenesulfonyl)-N,7-dimethyl-1,8,12-triazatricyclo[7.3.0.02,6]dodeca-2(6),7,9,11-tetraen-11-amine	482324: Displacement of [3H]lysergic acid diethylamide from human recombinant 5HT6 receptor expressed in human HeLa cells	ki	0.0002	uM
(4-oxo-2-azatricyclo[3.3.1.02,7]nonan-8-yl) 1H-indole-3-carboxylate	200911: Potency was evaluated on rabbit heart serotonergic receptors	kd	0.0002	uM
2-(1-naphthalen-2-ylsulfonylindol-6-yl)-3,4,8,8a-tetrahydro-1H-pyrrolo[1,2-a]pyrazine	239920: Binding affinity for human 5-hydroxytryptamine 6 receptor	ki	0.0002	uM
3-(benzenesulfonyl)-N,5,7-trimethylpyrazolo[1,5-a]pyrimidin-2-amine	590092: Displacement of [3H]lysergic acid diethylamide from human recombinant 5HT6 receptor	ki	0.0002	uM
[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methylurea	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
[(1R)-6-(benzenesulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
N-methyl-1-[(1R)-6-(1H-pyrrol-3-ylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-yl]methanamine	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
2-[[(1R)-8-fluoro-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methylamino]ethanol	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
[(1R)-8-fluoro-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methylurea	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
N-[[(1R)-6-(3-fluorophenyl)sulfonyl-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]-2-(methylamino)acetamide	484646: Displacement of [3H]LSD form human recombinant 5HT6 receptor	ki	0.0002	uM
1-[9-(2,5-dimethoxyphenyl)sulfonyl-6-methoxy-1,2,3,4-tetrahydrocarbazol-4-yl]-N,N-dimethylmethanamine	6525: Ability to displace [3H]LSD from human 5-hydroxytryptamine 6 receptor transiently expressed in COS-7 cells	ki	0.0003	uM
3-(3-chlorophenyl)sulfonyl-7-piperazin-1-yl-1H-indole	254607: Displacement of [3H]LSD from human 5-hydroxytryptamine 6 receptor expressed in HeLa cells	ki	0.0003	uM
1-(benzenesulfonyl)-4-piperazin-1-ylindole	1335238: Displacement of [3H]-LSD from human recombinant 5-HT6 receptor expressed in CHOK1 cell membranes measured after 60 mins by scintillation counter	ki	0.0003	uM
3-(3-fluorophenyl)sulfonyl-8-(4-methylpiperazin-1-yl)quinoline	1137930: Displacement of [3H]-LSD from human 5-HT6 receptor expressed in HEK293 cells	ki	0.0003	uM
1-(3-chlorophenyl)sulfonyl-4-piperazin-1-ylindole	254607: Displacement of [3H]LSD from human 5-hydroxytryptamine 6 receptor expressed in HeLa cells	ki	0.0003	uM
6-iodo-1-(4-methoxy-3-piperazin-1-ylphenyl)sulfonyl-2,3-dihydroindole	239920: Binding affinity for human 5-hydroxytryptamine 6 receptor	ki	0.0003	uM
4-iodo-N-[3-[[(2R)-1-methylpyrrolidin-2-yl]methyl]-1H-indol-5-yl]benzenesulfonamide	239580: Inhibition of [3H]LSD binding to human 5-hydroxytryptamine 6 receptor expressed in HeLa cells	ki	0.0003	uM
4-(2-fluorophenyl)sulfonyl-2,2-dimethyl-8-piperazin-1-yl-3H-1,4-benzoxazine	307663: Displacement of [3H]LSD from human recombinant 5HT6 receptor expressed in HEK293 cells	ki	0.0003	uM

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Clozapine	affects binding, affects cotreatment, increases expression	2
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	affects methylation	1
aflatoxin B2	increases methylation	1
SB 258585	affects binding	1
abrine	decreases expression	1
1-(5-fluoropentyl)-3-(1-naphthoyl)indole	affects binding	1
Olanzapine	affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cuprizone	affects cotreatment, increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Lead	increases expression	1
Lysergic Acid Diethylamide	affects binding	1
Methamphetamine	increases response to substance	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Risperidone	affects reaction, increases expression	1

ChEMBL screening assays

922 unique, capped per target: 688 binding, 228 functional, 6 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2060606	Binding	Inhibition of 5HT	Discovery and optimization of novel purines as potent and selective CB2 agonists. — Bioorg Med Chem Lett
CHEMBL4413391	ADMET	Antagonist activity at serotonin receptor in human PBMC assessed as inhibition of PMA-stimulated superoxide anion generation at 10 uM preincubated for 1 hr followed by PMA-stimulation and measured after 30 mins by spectrophotometric method	Identification of a novel DGKα inhibitor for XLP-1 therapy by virtual screening. — Eur J Med Chem
CHEMBL619167	Functional	5-HT level in K+ induced 5-hydroxytryptamine release in guinea pig cortex.	New selective and potent 5-HT(1B/1D) antagonists: chemistry and pharmacological evaluation of N-piperazinylphenyl biphenylcarboxamides and biphenylsulfonamides. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0T0	ACTOne HTR6	Transformed cell line	Female
CVCL_KZ28	PathHunter DLD1 HTR6 beta-arrestin	Cancer cell line	Male
CVCL_SR84	HAP1 HTR6 (-) 1	Cancer cell line	Male
CVCL_SR85	HAP1 HTR6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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