GPR6

Summary

GPR6 (G protein-coupled receptor 6, HGNC:4515) is a protein-coding gene on chromosome 6q21, encoding G-protein coupled receptor 6 (P46095). Constitutively active G-protein coupled receptor that maintains high cAMP levels and contributes to several processes including neuronal development, through activation of intracellular signaling pathways via G(s).

Predicted to enable sphingosine-1-phosphate receptor activity. Predicted to be involved in adenylate cyclase-activating G protein-coupled receptor signaling pathway and regulation of metabolic process. Predicted to act upstream of or within positive regulation of cytosolic calcium ion concentration. Predicted to be located in membrane. Predicted to be active in cytoplasm and plasma membrane.

Source: NCBI Gene 2830 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 52 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005284

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4515
Approved symbol	GPR6
Name	G protein-coupled receptor 6
Location	6q21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000146360
Ensembl biotype	protein_coding
OMIM	600553
Entrez	2830

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000275169, ENST00000414000

RefSeq mRNA: 2 — MANE Select: NM_005284 NM_001286099, NM_005284

CCDS: CCDS5079, CCDS69172

Canonical transcript exons

ENST00000275169 — 2 exons

Exon	Start	End
ENSE00002217544	109979095	109980720
ENSE00003920458	109978311	109978467

Expression profiles

Bgee: expression breadth broad, 51 present calls, max score 86.40.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6024 / max 138.3091, expressed in 67 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69245	0.5089	66
69244	0.0935	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	86.40	gold quality
putamen	UBERON:0001874	85.68	gold quality
caudate nucleus	UBERON:0001873	82.59	gold quality
middle frontal gyrus	UBERON:0002702	79.93	gold quality
endothelial cell	CL:0000115	78.51	gold quality
middle temporal gyrus	UBERON:0002771	69.97	gold quality
Brodmann (1909) area 23	UBERON:0013554	69.12	gold quality
lateral globus pallidus	UBERON:0002476	66.53	gold quality
Brodmann (1909) area 10	UBERON:0013541	64.93	gold quality
pituitary gland	UBERON:0000007	63.65	gold quality
telencephalon	UBERON:0001893	63.10	gold quality
forebrain	UBERON:0001890	62.71	gold quality
entorhinal cortex	UBERON:0002728	62.36	gold quality
Brodmann (1909) area 9	UBERON:0013540	61.88	gold quality
prefrontal cortex	UBERON:0000451	61.49	gold quality
primary visual cortex	UBERON:0002436	61.43	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.85	gold quality
adenohypophysis	UBERON:0002196	60.11	gold quality
frontal cortex	UBERON:0001870	59.96	gold quality
right frontal lobe	UBERON:0002810	59.87	gold quality
neocortex	UBERON:0001950	59.09	gold quality
hypothalamus	UBERON:0001898	58.98	gold quality
cingulate cortex	UBERON:0003027	58.61	gold quality
anterior cingulate cortex	UBERON:0009835	58.37	gold quality
brain	UBERON:0000955	58.34	gold quality
central nervous system	UBERON:0001017	57.49	gold quality
superior frontal gyrus	UBERON:0002661	57.33	gold quality
cerebral cortex	UBERON:0000956	57.04	gold quality
decidua	UBERON:0002450	56.55	gold quality
occipital lobe	UBERON:0002021	56.15	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

92 targeting GPR6, 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-513A-5P	100.00	69.77	2465
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-545-3P	99.95	70.74	2783
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-106B-5P	99.88	74.72	2795

Literature-anchored findings (GeneRIF, showing 3)

• control of gene expression in vascular endothelial cells in the presence of fluid shear stress and determines that it is not a sphingosine 1-phosphate receptor (PMID:12649592)
• The GPR6 gene influences the reinforcement learning rate in a computational, neurogenetic model. (PMID:22487033)
• GPR6 Structural Insights: Homology Model Construction and Docking Studies. (PMID:32046081)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gpr6	ENSDARG00000052400
mus_musculus	Gpr6	ENSMUSG00000046922
rattus_norvegicus	Gpr6	ENSRNOG00000049580

Paralogs (18): LPAR2 (ENSG00000064547), CNR1 (ENSG00000118432), MC3R (ENSG00000124089), S1PR4 (ENSG00000125910), GPR12 (ENSG00000132975), GPR119 (ENSG00000147262), MC4R (ENSG00000166603), S1PR1 (ENSG00000170989), LPAR3 (ENSG00000171517), MC5R (ENSG00000176136), S1PR5 (ENSG00000180739), GPR3 (ENSG00000181773), MC2R (ENSG00000185231), CNR2 (ENSG00000188822), LPAR1 (ENSG00000198121), S1PR3 (ENSG00000213694), MC1R (ENSG00000258839), S1PR2 (ENSG00000267534)

Protein

Protein identifiers

G-protein coupled receptor 6 — P46095 (reviewed: P46095)

Alternative names: Sphingosine 1-phosphate receptor GPR6

All UniProt accessions (2): P46095, F1DAM6

UniProt curated annotations — full annotation on UniProt →

Function. Constitutively active G-protein coupled receptor that maintains high cAMP levels and contributes to several processes including neuronal development, through activation of intracellular signaling pathways via G(s). May be activated by lipid-derived agonists such as oleic acid or sphingosine 1-phosphate, leading to activation of the G(s)/cAMP/PKA signaling pathway.

Subunit / interactions. Interacts with GNAS.

Subcellular location. Cell membrane.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P46095-1	1	yes
P46095-2	2

RefSeq proteins (2): NP_001273028, NP_005275* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR000723	GPR_3/6/12_orphan	Family
IPR001151	GPR6	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (41 total): helix 10, topological domain 8, transmembrane region 7, modified residue 3, glycosylation site 3, sequence conflict 2, turn 2, strand 2, chain 1, lipid moiety-binding region 1, splice variant 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8TF5	X-RAY DIFFRACTION	2.1
8T1V	X-RAY DIFFRACTION	2.6
8TYW	ELECTRON MICROSCOPY	3.43
8T1W	X-RAY DIFFRACTION	3.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46095-F1	78.92	0.55

Antibody-complex structures (SAbDab): 1 — 8TYW

Functional residue map

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

Post-translational modifications (4): 356, 358, 360, 345

Glycosylation sites (3): 2, 9, 51

Mutagenesis-validated functional residues (1):

Position	Phenotype
166	strong decrease of gpr6-mediated signaling.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 115 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_SPHINGOLIPID_MEDIATED_SIGNALING_PATHWAY, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, MULLIGHAN_NPM1_SIGNATURE_3_DN, SCHLESINGER_H3K27ME3_IN_NORMAL_AND_METHYLATED_IN_CANCER, HILLION_HMGA1_TARGETS, GOBP_ADENYLATE_CYCLASE_ACTIVATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_BIOACTIVE_LIPID_RECEPTOR_ACTIVITY, YAGI_AML_WITH_T_8_21_TRANSLOCATION, GOMF_G_PROTEIN_COUPLED_RECEPTOR_ACTIVITY, MULLIGHAN_NPM1_MUTATED_SIGNATURE_1_DN, MARTENS_TRETINOIN_RESPONSE_UP, FIGUEROA_AML_METHYLATION_CLUSTER_1_UP, GOBP_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (5): G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), positive regulation of cytosolic calcium ion concentration (GO:0007204), sphingosine-1-phosphate receptor signaling pathway (GO:0003376), signal transduction (GO:0007165)

GO Molecular Function (2): G protein-coupled receptor activity (GO:0004930), sphingosine-1-phosphate receptor activity (GO:0038036)

GO Cellular Component (3): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
cellular anatomical structure	2
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
regulation of biological quality	1
sphingolipid mediated signaling pathway	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
sphingosine-1-phosphate receptor signaling pathway	1
bioactive lipid receptor activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1190 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GPR6	GRIK5	Q16478	850
GPR6	NR2E1	Q9Y466	823
GPR6	GPR88	Q9GZN0	760
GPR6	GRIK2	Q13002	672
GPR6	GPR55	Q9Y2T6	669
GPR6	GPR18	Q14330	635
GPR6	GPR52	Q9Y2T5	610
GPR6	ARRB2	P32121	576
GPR6	PPP1R1B	Q9UD71	479
GPR6	TRPV2	Q9Y5S1	478
GPR6	TRPM8	Q7Z2W7	461
GPR6	TRPA1	O75762	439
GPR6	GPR63	Q9BZJ6	438
GPR6	TRPV3	Q8NET8	434
GPR6	UNC5D	Q6UXZ4	427

IntAct

124 interactions, top by confidence:

A	B	Type	Score
GPR6	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	SYNJ2BP	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	GPR6	psi-mi:“MI:0407”(direct interaction)	0.440
AHNAK	GPR6	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	APBA2	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	CARD11	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	CASK	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	GPR6	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	DLG2	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
DLG4	GPR6	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	DLG5	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	FRMPD1	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
GPR6	FRMPD3	psi-mi:“MI:0407”(direct interaction)	0.440
FRMPD4	GPR6	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (2): HSPA8 (Affinity Capture-MS), EMC7 (Affinity Capture-MS)

ESM2 similar proteins: A0A287A2K5, F1MV99, O08858, O43193, O77808, O97772, P28646, P30098, P30552, P30553, P30796, P30872, P30873, P30937, P30938, P31391, P32239, P32300, P32307, P32745, P33533, P35346, P35370, P35377, P41143, P41146, P46095, P46627, P47748, P48044, P49660, P51651, P56481, P58406, P79266, P79292, Q49LX5, Q5D0K2, Q6W5G4, Q6YNI2

Diamond homologs: E7EM37, O02213, O02777, O08530, O42384, O73810, O95136, O95977, P14416, P18089, P19020, P19328, P20272, P20288, P21453, P21554, P22270, P24628, P28286, P30545, P30728, P30951, P34972, P34973, P35412, P35462, P46089, P46095, P46628, P47746, P47752, P47936, P48303, P51651, P52592, P52702, P52703, P53453, P56971, P60026

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 80 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	52.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	2e-06
Long-term potentiation	5	44.1×	2e-06
Assembly and cell surface presentation of NMDA receptors	9	42.3×	5e-11
Neurexins and neuroligins	10	36.5×	2e-11
Protein-protein interactions at synapses	6	29.5×	2e-06
RHOB GTPase cycle	5	14.3×	5e-04

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	74.5×	2e-14
protein localization to synapse	6	58.9×	7e-08
receptor clustering	7	56.0×	7e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	44.5×	3e-08
bicellular tight junction assembly	5	21.2×	2e-04
protein-containing complex assembly	9	13.1×	2e-06
cell-cell adhesion	10	13.0×	4e-07
protein localization to plasma membrane	8	11.2×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	1
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

225 predictions. Top by Δscore:

Variant	Effect	Δscore
6:109979391:G:GA	donor_gain	0.7600
6:109979390:T:TA	donor_gain	0.6800
6:109979273:TGGAG:T	acceptor_gain	0.6100
6:109979507:A:AG	acceptor_gain	0.6100
6:109979508:G:GG	acceptor_gain	0.6100
6:109979151:G:GA	donor_gain	0.5800
6:109979508:GT:G	acceptor_gain	0.5800
6:109979330:A:G	donor_gain	0.5700
6:109979150:T:TA	donor_gain	0.5500
6:109979152:GTG:G	donor_gain	0.5500
6:109979444:T:TA	donor_gain	0.5500
6:109979445:A:AA	donor_gain	0.5500
6:109979432:T:G	donor_gain	0.5100
6:109979447:G:GT	donor_gain	0.5000
6:109979844:G:GG	donor_gain	0.5000
6:109979329:AATCC:A	donor_gain	0.4900
6:109979154:G:GA	donor_gain	0.4800
6:109979441:T:TA	donor_gain	0.4800
6:109979510:ACTT:A	acceptor_gain	0.4800
6:109979156:T:TA	donor_gain	0.4700
6:109979157:A:AA	donor_gain	0.4700
6:109979274:GGAGC:G	acceptor_gain	0.4700
6:109979940:GGGT:G	donor_gain	0.4700
6:109979941:GGTG:G	donor_gain	0.4700
6:109979443:G:GG	donor_gain	0.4600
6:109979864:T:TA	donor_gain	0.4500
6:109979338:G:T	donor_gain	0.4400
6:109979448:C:T	donor_gain	0.4400
6:109979865:G:GA	donor_gain	0.4400
6:109979942:GT:G	donor_gain	0.4400

AlphaMissense

2273 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:109979359:G:T	G83W	0.999
6:109979360:G:A	G83E	0.999
6:109979382:C:A	N90K	0.999
6:109979382:C:G	N90K	0.999
6:109979449:A:C	S113R	0.999
6:109979451:C:A	S113R	0.999
6:109979451:C:G	S113R	0.999
6:109979465:A:T	D118V	0.999
6:109979584:A:C	S158R	0.999
6:109979586:C:A	S158R	0.999
6:109979586:C:G	S158R	0.999
6:109979359:G:A	G83R	0.998
6:109979359:G:C	G83R	0.998
6:109979381:A:T	N90I	0.998
6:109979465:A:C	D118A	0.998
6:109980065:C:A	A318D	0.998
6:109980089:C:A	P326H	0.998
6:109979380:A:C	N90H	0.997
6:109979380:A:T	N90Y	0.997
6:109979465:A:G	D118G	0.997
6:109979466:C:A	D118E	0.997
6:109979466:C:G	D118E	0.997
6:109979476:G:C	G122R	0.997
6:109979477:G:A	G122D	0.997
6:109979983:A:C	S291R	0.997
6:109979985:C:A	S291R	0.997
6:109979985:C:G	S291R	0.997
6:109979986:T:A	W292R	0.997
6:109979986:T:C	W292R	0.997
6:109979993:C:A	P294H	0.997

dbSNP variants (sampled 300 via entrez): RS1000054218 (6:109978632 C>T), RS1000127486 (6:109977480 A>T), RS1001801086 (6:109980482 A>G), RS1002133726 (6:109980071 A>G), RS1003519718 (6:109976845 A>G), RS1003907349 (6:109978259 C>G), RS1004146420 (6:109979755 G>A,C,T), RS1004257860 (6:109978069 C>T), RS1005992796 (6:109979556 C>A,G,T), RS1006636978 (6:109977559 G>A), RS1006705540 (6:109976340 T>A), RS1006759607 (6:109976684 C>A,T), RS1007669265 (6:109976372 G>A), RS1008760003 (6:109979235 G>A,C,T), RS1008827526 (6:109981166 T>A)

Disease associations

OMIM: gene MIM:600553 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007576_334	Chronotype	3.000000e-10
GCST009391_1803	Metabolite levels	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0010403	triacylglycerol 48:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3714130 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,963 (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
CHEMBL2387742	CANNABIDIVARIN	2	4,963

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Class A Orphans with emerging pharmacology

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
example 494 [WO2014028479] parent molecule	Inverse agonist	8.7	pIC50
solengepras	Inverse agonist	8.03	pKi
sphingosine 1-phosphate	Full agonist	7.66	pEC50
example 31 [WO2018183145]	Inverse agonist	7.1	pEC50

Binding affinities (BindingDB)

2 measured of 2 human assays (2 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[[(3S)-oxolan-3-yl]amino]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone	IC50	505 nM	US-10406157: Tetrahydropyridopyrazine modulators of GPR6
US10406157, Compound Formula 1	IC50	1970 nM	US-10406157: Tetrahydropyridopyrazine modulators of GPR6

ChEMBL bioactivities

1022 potent at pChembl≥5 of 1233 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.98	IC50	0.0104	nM	CHEMBL3909497
10.98	IC50	0.0104	nM	CHEMBL3892898
10.94	IC50	0.0115	nM	CHEMBL3931736
10.94	IC50	0.0114	nM	CHEMBL3890613
10.92	IC50	0.012	nM	CHEMBL3905204
10.87	IC50	0.0134	nM	CHEMBL3962092
10.86	IC50	0.0138	nM	CHEMBL3971468
10.86	IC50	0.0137	nM	CHEMBL3982858
10.86	IC50	0.0138	nM	CHEMBL3955078
10.86	IC50	0.0138	nM	CHEMBL3915516
10.83	IC50	0.0149	nM	CHEMBL3957710
10.82	IC50	0.0152	nM	CHEMBL3935897
10.78	IC50	0.0166	nM	CHEMBL3976386
10.77	IC50	0.0168	nM	CHEMBL3943282
10.77	IC50	0.0171	nM	CHEMBL3930473
10.76	IC50	0.0173	nM	CHEMBL3967591
10.75	IC50	0.0179	nM	CHEMBL3908467
10.74	IC50	0.018	nM	CHEMBL3963072
10.73	IC50	0.0185	nM	CHEMBL4113017
10.71	IC50	0.0195	nM	CHEMBL3986433
10.71	IC50	0.0197	nM	CHEMBL3925720
10.70	IC50	0.0199	nM	CHEMBL3943478
10.68	IC50	0.0209	nM	CHEMBL3949818
10.66	IC50	0.0221	nM	CHEMBL3905140
10.64	IC50	0.023	nM	CHEMBL3923125
10.63	IC50	0.0237	nM	CHEMBL3921525
10.63	IC50	0.0232	nM	CHEMBL3985327
10.63	IC50	0.0236	nM	CHEMBL4113420
10.62	IC50	0.0239	nM	CHEMBL3967336
10.61	IC50	0.0246	nM	CHEMBL3973483
10.60	IC50	0.0249	nM	CHEMBL3948026
10.60	IC50	0.0249	nM	CHEMBL3945233
10.58	IC50	0.0266	nM	CHEMBL3911615
10.58	IC50	0.0265	nM	CHEMBL4111582
10.57	IC50	0.0269	nM	CHEMBL3924362
10.57	IC50	0.027	nM	CHEMBL3937342
10.56	IC50	0.0274	nM	CHEMBL3965180
10.56	IC50	0.0276	nM	CHEMBL3965158
10.55	IC50	0.0279	nM	CHEMBL3946230
10.54	IC50	0.029	nM	CHEMBL3892902
10.53	IC50	0.0298	nM	CHEMBL3945303
10.52	IC50	0.0303	nM	CHEMBL3934607
10.51	IC50	0.0309	nM	CHEMBL3975542
10.50	IC50	0.0314	nM	CHEMBL3975976
10.49	IC50	0.0327	nM	CHEMBL3927473
10.49	IC50	0.0325	nM	CHEMBL3951645
10.47	IC50	0.0337	nM	CHEMBL3973483
10.46	IC50	0.035	nM	CHEMBL3935030
10.44	IC50	0.0359	nM	CHEMBL3954223
10.42	IC50	0.0378	nM	CHEMBL4107203

PubChem BioAssay actives

14 with measured affinity, of 55 total; 12 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
N-cyclopropyl-3-[4-[(2,4-difluorophenyl)methyl]piperazin-1-yl]pyrido[3,4-b]pyrazin-2-amine	1816587: Displacement of 3H-RL338 from human GPR6 expressed in T-REx-CHO-GPR6 cells assessed as inhibition constant by competition binding assay	ki	0.0070	uM
1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-[[(3R)-oxolan-3-yl]amino]-7,8-dihydro-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone	1816587: Displacement of 3H-RL338 from human GPR6 expressed in T-REx-CHO-GPR6 cells assessed as inhibition constant by competition binding assay	ki	0.0094	uM
5-[6-[2-[7-[(4-chloro-2-propan-2-yloxyphenyl)methylamino]-[1,2,4]triazolo[1,5-a]pyrimidin-5-yl]phenoxy]hexylcarbamoyl]-2-[3-(dimethylamino)-6-dimethylazaniumylidenexanthen-9-yl]benzoate	2021317: Competitive total binding affinity to full-length wild-type human brain GPR6 expressed in HEK293A cells using furimazine as substrate at 1 uM measured for 3 hrs in presence of CVN424 by NanoBRET assay	ki	0.0132	uM
1-[2-[4-(2,4-difluorophenoxy)piperidin-1-yl]-3-(propan-2-ylamino)-5H-pyrido[3,4-b]pyrazin-6-yl]ethanone	1816587: Displacement of 3H-RL338 from human GPR6 expressed in T-REx-CHO-GPR6 cells assessed as inhibition constant by competition binding assay	ki	0.0160	uM
N-cyclopropyl-3-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]pyrido[3,4-b]pyrazin-2-amine	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	0.0530	uM
N-cyclopropyl-2-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]pyrido[3,4-b]pyrazin-3-amine	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	0.0550	uM
2-(cyclopropylamino)-3-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]-N,N-dimethylquinoxaline-6-carboxamide	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	0.0900	uM
3-(cyclopropylamino)-2-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]quinoxaline-6-carbonitrile	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	0.1740	uM
N-cyclopropyl-3-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]-7-fluoroquinoxalin-2-amine	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	1.2000	uM
N-cyclopropyl-3-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]quinoxalin-2-amine	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	2.1000	uM
2-[(1R,6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-propylbenzene-1,3-diol	1845632: Binding affinity to human GPR6 expressed in HEK293 cells assessed as reduction in cAMP level incubated for 1 hr by HTRF assay	ec50	2.4000	uM
N-cyclopropyl-3-[4-[(2,5-dichlorophenyl)methyl]piperazin-1-yl]-7-methoxyquinoxalin-2-amine	1816580: Inverse agonist activity at human GPR6 expressed in CHO-K1 cells assessed as modulation of cAMP level incubated for 20 hrs by TR-FRET assay	ec50	4.1000	uM

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
CD 437	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Folic Acid	decreases expression	1
Zinc	decreases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

36 unique, capped per target: 21 functional, 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3720810	Functional	Inverse agonist activity at rat G-protein GSalpha fused GPR6 (unknown origin) expressed in HEK293 cell membranes assessed as effect on [35S]GTPgammaS binding pre-incubated for 5 to 10 mins followed by 60 mins incubation in presence of [35S]	Small molecule modulators of g protein-coupled receptor six
CHEMBL4742498	Binding	Binding affinity to GPR6 (unknown origin) expressed in CHO-K1 cells by liquid scintillation counting based competition binding assay	Tetrahydropyridopyrazine modulators of GPR6

Cellosaurus cell lines

2 cell lines: 1 spontaneously immortalized cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KX68	PathHunter CHO-K1 GPR6 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LA45	PathHunter U2OS GPR6 beta-arrestin	Cancer cell line	Female

Clinical trials (associated diseases)

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