HCRTR1

Summary

HCRTR1 (hypocretin receptor 1, HGNC:4848) is a protein-coding gene on chromosome 1p35.2, encoding Orexin/Hypocretin receptor type 1 (O43613). G-protein coupled receptor that binds the neuropeptide orexin-A with high affinity, and orexin-B with lower affinity, two peptides derived from a common precursor, prepro-orexin.

The protein encoded by this gene is a G-protein coupled receptor involved in the regulation of feeding behavior. The encoded protein selectively binds the hypothalamic neuropeptide orexin A. A related gene (HCRTR2) encodes a G-protein coupled receptor that binds orexin A and orexin B.

Source: NCBI Gene 3061 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated cerebellar hypoplasia/agenesis (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 279 total — 2 pathogenic
• Druggable target: yes — 13 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001525

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4848
Approved symbol	HCRTR1
Name	hypocretin receptor 1
Location	1p35.2
Locus type	gene with protein product
Status	Approved
Aliases	OX1R, OXR1, ORXR1
Ensembl gene	ENSG00000121764
Ensembl biotype	protein_coding
OMIM	602392
Entrez	3061

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000373705, ENST00000373706, ENST00000403528, ENST00000468521, ENST00000485464, ENST00000686354, ENST00000971603, ENST00000971604

RefSeq mRNA: 1 — MANE Select: NM_001525 NM_001525

CCDS: CCDS344

Canonical transcript exons

ENST00000403528 — 9 exons

Exon	Start	End
ENSE00000437378	31619532	31619710
ENSE00001560945	31617689	31617881
ENSE00001561452	31618756	31618816
ENSE00001563642	31626790	31627613
ENSE00003515394	31624997	31625118
ENSE00003551218	31620843	31621086
ENSE00003624025	31621477	31621592
ENSE00003674905	31623523	31623749
ENSE00003680717	31619051	31619391

Expression profiles

Bgee: expression breadth ubiquitous, 113 present calls, max score 82.05.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1304 / max 17.2287, expressed in 51 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1929	0.1304	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
vastus lateralis	UBERON:0001379	82.05	gold quality
quadriceps femoris	UBERON:0001377	79.06	gold quality
apex of heart	UBERON:0002098	71.19	gold quality
cerebellar vermis	UBERON:0004720	69.53	gold quality
epithelium of bronchus	UBERON:0002031	69.47	gold quality
cortical plate	UBERON:0005343	69.07	gold quality
trachea	UBERON:0003126	63.65	gold quality
hair follicle	UBERON:0002073	61.06	gold quality
primary visual cortex	UBERON:0002436	60.42	gold quality
palpebral conjunctiva	UBERON:0001812	59.99	gold quality
superior frontal gyrus	UBERON:0002661	59.97	gold quality
right lobe of thyroid gland	UBERON:0001119	59.88	gold quality
placenta	UBERON:0001987	59.81	gold quality
decidua	UBERON:0002450	59.58	gold quality
prefrontal cortex	UBERON:0000451	59.25	gold quality
left lobe of thyroid gland	UBERON:0001120	59.24	gold quality
dorsal plus ventral thalamus	UBERON:0001897	59.03	gold quality
dorsal root ganglion	UBERON:0000044	58.67	gold quality
bone marrow cell	CL:0002092	58.46	gold quality
thyroid gland	UBERON:0002046	58.27	gold quality
heart left ventricle	UBERON:0002084	58.02	gold quality
layer of synovial tissue	UBERON:0007616	57.91	gold quality
thymus	UBERON:0002370	57.74	gold quality
skeletal muscle tissue	UBERON:0001134	57.70	gold quality
hypothalamus	UBERON:0001898	57.64	gold quality
muscle of leg	UBERON:0001383	56.67	gold quality
frontal cortex	UBERON:0001870	56.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	56.23	gold quality
gastrocnemius	UBERON:0001388	56.19	gold quality
endometrium epithelium	UBERON:0004811	56.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting HCRTR1, 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-12118	100.00	65.88	1270
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-3164	99.02	68.39	1071
HSA-MIR-6820-3P	99.02	68.50	1035
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-6894-5P	98.70	63.78	809
HSA-MIR-6830-3P	98.62	68.07	1760
HSA-MIR-4266	98.53	67.29	1035
HSA-MIR-4712-3P	98.52	65.39	822
HSA-MIR-548S	98.50	67.17	1213
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-5585-5P	97.95	68.80	1024
HSA-MIR-6824-5P	97.41	68.43	583
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-6854-5P	96.77	65.96	848
HSA-MIR-6738-5P	96.33	63.61	815
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-1914-3P	95.07	63.37	762
HSA-MIR-1229-5P	94.57	65.78	487

Literature-anchored findings (GeneRIF, showing 40)

• The SK-N-MC cell line expresses an orexin binding site different from recombinant orexin 1-type receptor. (PMID:11856342)
• evidence that CB1 is able to potentiate an orexigenic receptor, OX1R (PMID:12690115)
• both OX1R and OX2R are expressed in the testis, epididymis, penis, and seminal vesicle (PMID:15070969)
• OX(1) receptors stimulate adenylyl cyclase via a low potency G(s) coupling and a high potency phospholipase C –> PKC coupling. (PMID:15611118)
• All adrenal corttex adenomas expressed OX1-R and OX2-R mRNAs, and real-time PCR showed that the expression of both receptors was up-regulated in adenomas (PMID:15797953)
• Our preliminary data suggest that mutation hcrtr1 might have an increased susceptibility to polydipsia through an undetermined mechanism. (PMID:15978554)
• Orexins act exclusively through OX1-receptors coupled to the adenylate cyclase/protein kinase A-dependent signaling cascade. (PMID:16157481)
• OX1 orexin/hcrtr-1 hypocretin receptors induce caspase-dependent and -independent cell death through p38 mitogen-/stress-activated protein kinase (PMID:16282319)
• This is the first demonstration of loss of Hcrt/Orx neurons in MSA, which is consistent with a system degeneration of neurons involved in homeostatic function, including sleep and autonomic regulation, in this disorder. (PMID:17089135)
• Results support the hypothesis that the HCRTR1 Ile408Val polymorphism may confer susceptibility to polydipsia in schizophrenia. (PMID:17999203)
• orexin-induced apoptosis is driven by an immunoreceptor tyrosine-based inhibitory motif (ITIM) present in the OX1R and is mediated by SHP-2 phosphatase recruitment via a mechanism that requires Gq protein but is independent of phospholipase C activation. (PMID:18198212)
• Orexin effects on StAR were primarily, but not exclusively, acting through the orexin receptor type 1. (PMID:18450961)
• Both sporadic narcoleptic dogs and human narcolepsy-cataplexy subjects showed a significant decrease in hcrtR1 expression, while declines in hcrtR2 expression were not significant in these cases. (PMID:18714784)
• Induction of intracellular calcium signaling in isolated duodenal enterocytes is mediated primarily by OX1R receptors (PMID:19118115)
• OX1R are able to activate TRPC(3)-channel-dependent oscillatory responses independently of store discharge. (PMID:19464259)
• It was shown here that another motif, immunoreceptor tyrosine-based switch motif, is present in orexin receptor-1 (OX1R) and is mandatory for OX1R-mediated apoptosis. (PMID:19661287)
• OX1 orexin receptor activation results in robust arachidonic acid release. (PMID:20002100)
• Data demonstrate the functional role of protein kinase D1 and protein kinase D3 in modulating physiological responses to Ox1R activation. (PMID:20621130)
• In differentiated IMR-32 neuroblastoma cells orexin/hypocretin and bradykinin receptors activate TRPC3/6 channels. (PMID:20728215)
• Data show that the HCRTR1 gene or a linked locus may modulate the risk for Major Mood Disorders and supports recent studies suggesting an involvement of hypocretin neurotransmitter system in affective disorders. (PMID:21071097)
• decreased ventilatory responses to hypoxia in human narcolepsy-cataplexy is in relation to HLA-DQB1*0602 status, not hypocretin deficiency (PMID:21318258)
• HCRTR1 gene could represent a genetic susceptibility factor for migraine without aura; the hypocretin system may have a role in the pathophysiology of migraine. (PMID:21344296)
• analysis of orexin receptor 1 and 2 -arrestin-ubiquitin complexes (PMID:21378163)
• Results show that the N-terminal regions of orexin receptor are most important, and the exchange of the area from the C-terminal part of the transmembrane helix 2 to the transmembrane helix 4 is enough to lead to a change of the receptor’s ligand profile. (PMID:21510948)
• The Ile408Val polymorphism in the hypocretin receptor 1 (HCRTR1) gene and the Val308Iso (G1246A) polymorphism in the hypocretin receptor 2 (HCRTR2) gene in a sample of 215 panic disorder patients and 454 controls, were analyzed. (PMID:21666548)
• Heteromultimerization of cannabinoid CB(1) receptor and orexin OX(1) receptor generates a unique complex in which both protomers are regulated by orexin A. (PMID:21908614)
• Dynlt1 modulates orexin signaling by regulating OX1R (PMID:22028875)
• Intramolecular fluorescence resonance energy transfer (FRET) sensors of the orexin OX1 and OX2 receptors identify slow kinetics of agonist activation. (PMID:22389503)
• Orexin receptors generate potent endocannabinoid signals in addition to arachidonic acid signals, which may explain the proposed orexin-cannabinoid interactions. (PMID:22550093)
• [review] Native orexin peptides consist of receptor agonists, orexin-A (33 amino acids) and orexin-B (28 amino acids) (aka hypocretin-1 and hypocretin-2). (PMID:23034387)
• DQ B1 but not HLA-DR typing, TNF-alpha levels, HCRTR1 and HCRTR2 were higher in narcolepsy-cataplexy/schizophrenia patients. (PMID:24268496)
• Orexins modifiy orexin receptor gene expression and gonadotropin release from the anterior pituitary gland. (PMID:24333629)
• Both orexin receptor subtypes, OX1R and OX2R, and CB1 cannabinoid receptors are capable of forming constitutive homo- and heteromeric complexes. (PMID:24530395)
• The present data indicate that OX1R-driven apoptosis is overexpressed in androgeno-independent prostate cancer exhibiting a neuroendocrine differentiation opening a gate for novel therapies for these aggressive cancers which are incurable until now. (PMID:24910418)
• No significant differences were found in the distribution of either genotypic or allelic frequencies between Alzheimer’s disease cases and controls in the HCRTR1 polymorphisms. (PMID:24969517)
• Orexin receptor binding was strongly dependent on the extracellular Ca(2+) concentration. (PMID:25132134)
• Decrease in Ox expression with normal human maturation and aging. This may contribute to changes in sleep regulation during development and with aging. (PMID:25212464)
• Orexin A upregulates the protein expression of OX1R and enhances the proliferation of SGC-7901 gastric cancer cells through the ERK signaling pathway. (PMID:25515760)
• Data suggest that interaction between the nociceptin/nociceptin receptor system and the orexin/orexin receptor system in neurons of the hypothalamus positively and negatively modulate complex and integrated responses to stress. [REVIEW] (PMID:25677777)
• OX1R signaling can attenuate KOR-mediated reduction of cellular cAMP levels while enhancing KOR-mediated beta-arrestin recruitment and p38 activation. (PMID:25857454)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcrtr1	ENSMUSG00000028778
rattus_norvegicus	Hcrtr1	ENSRNOG00000013838

Paralogs (16): NPFFR2 (ENSG00000056291), GNRHR (ENSG00000109163), CCKBR (ENSG00000110148), AVPR2 (ENSG00000126895), GALR3 (ENSG00000128310), HCRTR2 (ENSG00000137252), NPFFR1 (ENSG00000148734), CCKAR (ENSG00000163394), AVPR1A (ENSG00000166148), GALR1 (ENSG00000166573), GPR22 (ENSG00000172209), GPR150 (ENSG00000178015), OXTR (ENSG00000180914), FFAR4 (ENSG00000186188), QRFPR (ENSG00000186867), AVPR1B (ENSG00000198049)

Protein

Protein identifiers

Orexin/Hypocretin receptor type 1 — O43613 (reviewed: O43613)

Alternative names: Hypocretin receptor type 1, Orexin receptor type 1

All UniProt accessions (3): A0A8I5KTU6, A6NMV7, O43613

UniProt curated annotations — full annotation on UniProt →

Function. G-protein coupled receptor that binds the neuropeptide orexin-A with high affinity, and orexin-B with lower affinity, two peptides derived from a common precursor, prepro-orexin. Its activity is mediated via a G(q)-protein-coupled pathway, which activates the phosphatidylinositol-calcium second messenger system in response to orexin-A binding. In addition to G(q)-mediated signaling, orexin-A stimulation also promotes beta-arrestin recruitment, leading to receptor internalization. Plays a significant role in the regulation of food intake.

Subcellular location. Cell membrane.

Domain organisation. The N-terminal region is required for orexin signaling.

Miscellaneous. The antagonists suvorexant and SB-674042 bind at the cognate neuropeptide binding site that is situated between the transmembrane helices and accessible from the extracellular side of the membrane.

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

RefSeq proteins (1): NP_001516* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000204	Orexin_rcpt	Family
IPR000276	GPCR_Rhodpsn	Family
IPR004059	OX1R	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (53 total): helix 16, topological domain 8, transmembrane region 7, sequence variant 4, mutagenesis site 4, strand 4, region of interest 2, site 2, chain 1, binding site 1, glycosylation site 1, disulfide bond 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
6TOD	X-RAY DIFFRACTION	2.11
6TOS	X-RAY DIFFRACTION	2.13
6TOT	X-RAY DIFFRACTION	2.22
6TO7	X-RAY DIFFRACTION	2.26
6TQ4	X-RAY DIFFRACTION	2.3
6TP6	X-RAY DIFFRACTION	2.34
6TQ6	X-RAY DIFFRACTION	2.55
6TQ9	X-RAY DIFFRACTION	2.65
6TQ7	X-RAY DIFFRACTION	2.66
4ZJ8	X-RAY DIFFRACTION	2.75
4ZJC	X-RAY DIFFRACTION	2.83
6TP4	X-RAY DIFFRACTION	3.01
6TP3	X-RAY DIFFRACTION	3.04
6V9S	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43613-F1	79.62	0.55

Functional residue map

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

Catalytic / active sites (2): 36 (important for responses to orexin); 127 (critical for hcrtr1 selectivity over hcrtr2)

Ligand- & substrate-binding residues (1): 318

Disulfide bonds (1): 119–202

Glycosylation sites (1): 194

Mutagenesis-validated functional residues (4):

Position	Phenotype
26–41	abolishes response to orexin-a.
36	strongly impairs response to orexin-a.
127	confers empa binding. decreases affinity for the selective ligand jh112. the affinity of antagonist suvorexant is slight
318	strongly impairs response to orexin-a.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-389397	Orexin and neuropeptides FF and QRFP bind to their respective receptors
R-HSA-416476	G alpha (q) signalling events

MSigDB gene sets: 381 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE45365_NK_CELL_VS_BCELL_DN, WENDT_COHESIN_TARGETS_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, RNGTGGGC_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, AAGCAAT_MIR137, GOBP_BEHAVIOR, MODULE_545, GCANCTGNY_MYOD_Q6, GOBP_ADULT_BEHAVIOR, AREB6_03, MAZ_Q6, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (8): neuropeptide signaling pathway (GO:0007218), chemical synaptic transmission (GO:0007268), feeding behavior (GO:0007631), cellular response to hormone stimulus (GO:0032870), regulation of cytosolic calcium ion concentration (GO:0051480), positive regulation of ERK1 and ERK2 cascade (GO:0070374), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (4): G protein-coupled receptor activity (GO:0004930), orexin receptor activity (GO:0016499), peptide hormone binding (GO:0017046), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), synapse (GO:0045202), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Peptide ligand-binding receptors	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
anterograde trans-synaptic signaling	1
behavior	1
response to hormone	1
cellular response to chemical stimulus	1
cellular response to endogenous stimulus	1
intracellular calcium ion homeostasis	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
transmembrane signaling receptor activity	1
G protein-coupled peptide receptor activity	1
hormone binding	1
binding	1
membrane	1
cell periphery	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

730 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCRTR1	HCRT	O43612	999
HCRTR1	OXR1	Q8N573	793
HCRTR1	PMCH	P20382	755
HCRTR1	ATXN3L	Q9H3M9	709
HCRTR1	PDYN	P01213	706
HCRTR1	CNR1	P21554	694
HCRTR1	CRHR1	P34998	682
HCRTR1	POMC	P01189	653
HCRTR1	CRH	P06850	646
HCRTR1	OR13H1	Q8NG92	643
HCRTR1	ATXN3	P54252	633
HCRTR1	SCT	P09683	587
HCRTR1	FOS	P01100	576
HCRTR1	NPY	P01303	571
HCRTR1	NPTX2	P47972	556

IntAct

17 interactions, top by confidence:

A	B	Type	Score
HCRTR1	LEPR	psi-mi:“MI:0403”(colocalization)	0.580
HCRTR1	LEPR	psi-mi:“MI:2364”(proximity)	0.580
LEPR	HCRTR1	psi-mi:“MI:0915”(physical association)	0.580
APLNR	HCRTR1	psi-mi:“MI:0915”(physical association)	0.560
HCRTR1	APLNR	psi-mi:“MI:0915”(physical association)	0.560
HCRTR1	APLNR	psi-mi:“MI:0403”(colocalization)	0.560
APLNR	HCRTR1	psi-mi:“MI:0403”(colocalization)	0.560
HCRTR1	GHSR	psi-mi:“MI:0403”(colocalization)	0.440
GHSR	HCRTR1	psi-mi:“MI:2364”(proximity)	0.440
HCRTR1	OPRK1	psi-mi:“MI:0915”(physical association)	0.400
HCRTR1	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	HCRTR1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (7): NPR1 (Negative Genetic), PIK3C2B (Negative Genetic), HCRTR1 (Negative Genetic), HCRTR1 (Positive Genetic), HCRTR1 (Affinity Capture-MS), ARRB2 (FRET), ARRB1 (FRET)

ESM2 similar proteins: A1ZAX0, O02835, O02836, O08786, O43613, O43614, O46639, O62809, O93603, O97772, P0C0L6, P21761, P25931, P28646, P30551, P30560, P30872, P30873, P30975, P32238, P32247, P34981, P37288, P47751, P48043, P49146, P56719, P58307, P58308, P70031, P79113, P97295, Q1RMU8, Q28596, Q49LX5, Q4V622, Q5D0K2, Q5IS62, Q61041, Q62463

Diamond homologs: A1ZAX0, B1PHQ8, B9VR26, E7F7V7, F1MV99, F1R332, O02836, O08726, O08858, O35786, O43603, O43613, O60755, O88626, O88853, O88854, O97512, O97661, O97666, P0C7U5, P16177, P21109, P25103, P28646, P29371, P30098, P30547, P30680, P30872, P30873, P30874, P30875, P30935, P30936, P30937, P30938, P30974, P30975, P31391, P32250

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
1-(6,8-difluoro-2-methyl-4-quinolinyl)-3-[4-(dimethylamino)phenyl]urea	down-regulates	HCRTR1	“chemical inhibition”
HCRTR1	“up-regulates activity”	GNAI1	binding
HCRTR1	“up-regulates activity”	GNAI3	binding
HCRTR1	“up-regulates activity”	GNAO1	binding
HCRTR1	“up-regulates activity”	GNAZ	binding
HCRTR1	“up-regulates activity”	GNAQ	binding
HCRTR1	“up-regulates activity”	GNA14	binding
HCRTR1	“up-regulates activity”	GNA15	binding
HCRTR1	“up-regulates activity”	GNA12	binding
“Orexin A”	“up-regulates activity”	HCRTR1	“chemical activation”
CNR1	“up-regulates activity”	HCRTR1	binding
HCRT	up-regulates	HCRTR1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	203
Likely benign	25
Benign	5

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
694396	NM_001198533.2(OXR1):c.1100C>G (p.Ser367Ter)	Pathogenic
694397	NM_001198533.2(OXR1):c.2163+1G>T	Pathogenic

SpliceAI

2023 predictions. Top by Δscore:

Variant	Effect	Δscore
1:31619530:A:AG	acceptor_gain	1.0000
1:31619531:G:GC	acceptor_gain	1.0000
1:31619531:GTC:G	acceptor_gain	1.0000
1:31619531:GTCT:G	acceptor_gain	1.0000
1:31619601:T:TA	acceptor_gain	1.0000
1:31619709:AG:A	donor_loss	1.0000
1:31619710:GGTG:G	donor_loss	1.0000
1:31619711:GTGAG:G	donor_loss	1.0000
1:31619712:T:G	donor_loss	1.0000
1:31623516:T:A	acceptor_gain	1.0000
1:31623519:ACAG:A	acceptor_loss	1.0000
1:31623521:A:AG	acceptor_gain	1.0000
1:31623521:AGA:A	acceptor_loss	1.0000
1:31623522:G:A	acceptor_loss	1.0000
1:31623522:G:GG	acceptor_gain	1.0000
1:31623747:GAG:G	donor_gain	1.0000
1:31623749:GGTG:G	donor_loss	1.0000
1:31623750:GT:G	donor_loss	1.0000
1:31624996:GGGT:G	acceptor_gain	1.0000
1:31625116:GTG:G	donor_gain	1.0000
1:31632489:CCGCA:C	donor_loss	1.0000
1:31632490:CGCA:C	donor_loss	1.0000
1:31632491:GCACC:G	donor_loss	1.0000
1:31632492:CACCT:C	donor_loss	1.0000
1:31632493:ACC:A	donor_loss	1.0000
1:31632494:C:CA	donor_loss	1.0000
1:31632494:CCTTG:C	donor_gain	1.0000
1:31617880:AG:A	donor_loss	0.9900
1:31617881:GGTG:G	donor_loss	0.9900
1:31617882:GTGC:G	donor_loss	0.9900

AlphaMissense

2738 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:31619593:C:A	N87K	0.999
1:31619593:C:G	N87K	0.999
1:31621082:G:C	W206C	0.999
1:31621082:G:T	W206C	0.999
1:31623703:T:C	F307L	0.999
1:31623705:C:A	F307L	0.999
1:31623705:C:G	F307L	0.999
1:31619688:G:A	C119Y	0.998
1:31620876:A:C	S138R	0.998
1:31620878:C:A	S138R	0.998
1:31620878:C:G	S138R	0.998
1:31620969:T:A	W169R	0.998
1:31620969:T:C	W169R	0.998
1:31621068:T:A	C202S	0.998
1:31621069:G:A	C202Y	0.998
1:31621069:G:C	C202S	0.998
1:31623722:C:G	P313R	0.998
1:31626795:T:C	F365L	0.998
1:31626797:C:A	F365L	0.998
1:31626797:C:G	F365L	0.998
1:31619586:T:A	I85N	0.997
1:31619595:T:C	L88P	0.997
1:31619687:T:A	C119S	0.997
1:31619688:G:C	C119S	0.997
1:31620895:G:C	R144P	0.997
1:31621567:T:A	I238K	0.997
1:31626796:T:G	F365C	0.997
1:31619578:C:A	N82K	0.996
1:31619578:C:G	N82K	0.996
1:31619639:A:C	S103R	0.996

dbSNP variants (sampled 300 via entrez): RS1000020448 (1:31627994 G>C), RS1000041346 (1:31622913 G>A), RS1000094998 (1:31622545 G>T), RS1000235200 (1:31616346 T>C), RS1000251485 (1:31634903 T>C), RS1000869305 (1:31621798 C>T), RS1001054179 (1:31615740 C>A), RS1001250792 (1:31630248 C>T), RS1001330146 (1:31621390 C>A), RS1001542504 (1:31624900 C>A,G,T), RS1001706818 (1:31630075 C>T), RS1001711581 (1:31624181 G>A), RS1001718060 (1:31618214 G>C), RS1001931816 (1:31622941 C>T), RS1001960597 (1:31617813 G>A)

Disease associations

OMIM: gene MIM:602392 | disease phenotypes: MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
isolated cerebellar hypoplasia/agenesis	Strong	Autosomal recessive
sensorineural hearing loss disorder	Strong	Autosomal recessive

Mondo (3): isolated cerebellar hypoplasia/agenesis (MONDO:0008939), hearing loss disorder (MONDO:0005365), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (2): Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246)

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST003263_121	Post bronchodilator FEV1 in COPD	4.000000e-06
GCST005141_37	Cognitive ability (MTAG)	8.000000e-10
GCST005142_60	Cognitive ability	5.000000e-08
GCST005352_27	Paclitaxel disposition in epithelial ovarian cancer	3.000000e-06
GCST005951_36	Body mass index	9.000000e-10
GCST006269_516	General cognitive ability	6.000000e-15
GCST006269_906	General cognitive ability	2.000000e-08
GCST006412_101	Intraocular pressure	2.000000e-09
GCST006412_75	Intraocular pressure	2.000000e-16
GCST009798_61	Asthma	3.000000e-08
GCST011494_2	Daytime nap	1.000000e-08
GCST012007_1	Hypoalbuminemia	1.000000e-06
GCST012167_6	Adiponectin levels	6.000000e-06
GCST90002385_368	High light scatter reticulocyte count	2.000000e-10
GCST90002386_488	High light scatter reticulocyte percentage of red cells	1.000000e-09
GCST90002405_518	Reticulocyte count	8.000000e-10

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004340	body mass index
EFO:0004695	intraocular pressure measurement
EFO:0007828	daytime rest measurement
EFO:0004502	adiponectin measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C562568	Cerebellar Hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL3301387 (PROTEIN COMPLEX), CHEMBL3307226 (PROTEIN FAMILY), CHEMBL5113 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

13 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,096 (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
CHEMBL1083659	SUVOREXANT	4	852
CHEMBL267495	NALFURAFINE	4	310
CHEMBL3545367	LEMBOREXANT	4	271
CHEMBL4297590	DARIDOREXANT	4	102
CHEMBL490665	NALFURAFINE HYDROCHLORIDE	4	107
CHEMBL3597971	SELTOREXANT	3	120
CHEMBL455136	ALMOREXANT	3	218
CHEMBL1272307	SB-649868	2	21
CHEMBL2107822	FILOREXANT	2	50
CHEMBL3892369	NIVASOREXANT	2	18
CHEMBL3338866	MK-1064	1	9
CHEMBL3597952	ACT-462206	1	11
CHEMBL3958101	CVN-766	1	7

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Orexin receptors

Most potent curated ligand interactions (42 total), top 25:

Ligand	Action	Affinity	Parameter
orexin-A	Full agonist	10.2	pEC50
daridorexant	Antagonist	9.5	pKB
SB-674042	Antagonist	9.3	pKi
orexin-B	Full agonist	9.2	pEC50
JH112	Antagonist	9.14	pKi
[3H]SB-674042	Antagonist	9.1	pKd
SB-649868	Antagonist	9.1	pKi
vornorexant	Antagonist	8.98	pIC50
[3H]-almorexant	Antagonist	8.9	pKd
1-SORA-51	Antagonist	8.74	pKi
suvorexant	Antagonist	8.7	pKB
filorexant	Antagonist	8.7	pKB
lemborexant	Antagonist	8.6	pKi
TCS 1102	Antagonist	8.52	pKB
danavorexton	Agonist	8.37	pEC50
[3H]-TCS 1102	Antagonist	8.2	pKd
(R)-YNT-3708	Agonist	8.11	pEC50
CVN766	Antagonist	8.1	pKi
CVN45502	Antagonist	7.9	pKi
almorexant	Antagonist	7.8	pKB
ACT-462206	Antagonist	7.8	pKB
SB-410220	Antagonist	7.7	pKi
fazamorexant	Antagonist	7.7	pIC50
RTOXA-43	Agonist	7.62	pEC50
Cp-1	Antagonist	7.59	pKi

Binding affinities (BindingDB)

5092 measured of 5441 human assays (5548 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[(2R,5R)-2-[(5-fluoro-2-pyridinyl)oxymethyl]-5-methylthiomorpholin-4-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	KI	0.38 nM	US-9029364: 2,5-disubstituted thiomorpholine orexin receptor antagonists
[4,5-dimethyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(3-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]methanone	IC50	0.4 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[4,5-dimethyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]methanone	IC50	0.5 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[5-(3-methoxyphenyl)-2-methyl-1,3-thiazol-4-yl]methanone	IC50	0.5 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone	IC50	0.5 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-[5-(3-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	0.6 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[4,5-dimethyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]methanone	IC50	0.6 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[2-methyl-5-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl]methanone	IC50	0.6 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[2-methyl-5-(3-methylphenyl)-1,3-thiazol-4-yl]methanone	IC50	0.6 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[4,5-dimethyl-2-(triazol-2-yl)phenyl]methanone	IC50	0.6 nM	US-9732075: Benzimidazole-proline derivatives
(4,5-Dimethyl-2-[1,2,3]triazol-2-yl-phenyl)-[(S)-2-(6-methoxy-1H-benzoimidazol-2-yl)-4-methylene-pyrrolidin-1-yl]-methanone	IC50	0.6 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-(4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[2-methyl-5-[3-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl]methanone	IC50	0.7 nM	US-9732075: Benzimidazole-proline derivatives
[5-(3-methoxyphenyl)-2-methyl-1,3-thiazol-4-yl]-[(2S)-2-(4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]methanone	IC50	0.7 nM	US-9732075: Benzimidazole-proline derivatives
[5-(3-bromophenyl)-2-methyl-1,3-thiazol-4-yl]-[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]methanone	IC50	0.7 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	0.7 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[5-(3-bromophenyl)-2-methyl-1,3-thiazol-4-yl]-[(2S)-2-(4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]methanone	IC50	0.8 nM	US-9732075: Benzimidazole-proline derivatives
[5-(3-bromo-4-fluorophenyl)-2-methyl-1,3-thiazol-4-yl]-[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]methanone	IC50	0.8 nM	US-9732075: Benzimidazole-proline derivatives
[(2S)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[5-(3,4-dichlorophenyl)-2-methyl-1,3-thiazol-4-yl]methanone	IC50	0.8 nM	US-9732075: Benzimidazole-proline derivatives
[(2R,5R)-2-[(5-fluoro-2-pyridinyl)oxymethyl]-5-methylthiomorpholin-4-yl]-[2-(triazol-2-yl)phenyl]methanone	KI	0.9 nM	US-9029364: 2,5-disubstituted thiomorpholine orexin receptor antagonists
[(2S)-2-(4-methyl-1H-benzimidazol-2-yl)-4-methylidenepyrrolidin-1-yl]-[2-methyl-5-(3-methylphenyl)-1,3-thiazol-4-yl]methanone	IC50	0.9 nM	US-9732075: Benzimidazole-proline derivatives
1-(dibenzofuran-2-ylmethyl)-6-(3,5-dimethoxy-4-pyridinyl)piperidin-2-one	IC50	1 nM	US-9242970: Lactam derivatives useful as orexin receptor antagonists
(3S,5S)-1-(dibenzofuran-2-ylmethyl)-5-(2,6-dimethoxyphenyl)-3-fluoropyrrolidin-2-one	IC50	1 nM	US-9242970: Lactam derivatives useful as orexin receptor antagonists
[2-[[4-(4-fluorophenyl)pyrazol-1-yl]methyl]-1,3-oxazinan-3-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9266870: Heteroaromatic methyl cyclic amine derivative
[2-[[3-(4-fluorophenyl)pyrazol-1-yl]methyl]-1,3-oxazinan-3-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone	IC50	1 nM	US-9266870: Heteroaromatic methyl cyclic amine derivative
[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]methanone	IC50	1 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[5-chloro-4-methyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]methanone	IC50	1 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]-[4,5-dimethyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]-[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]azetidin-1-yl]-[5-chloro-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9403813: Azetidine amide derivatives as orexin receptor antagonists
[4,5-dimethyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[3-(2-ethoxyphenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-1-yl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]-[(2S)-2-[3-(3-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-5-yl]pyrrolidin-1-yl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(2-ethoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-chloro-2-methylphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-chloro-2-methylphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[4,5-dimethyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(2-ethoxy-3-fluorophenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[4,5-dimethyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-fluorophenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-chloro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[4,5-dimethyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(3-fluoro-2-methoxyphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[5-chloro-4-methyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[5-(2-ethoxy-3-pyridinyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(2,5-dimethylphenyl)-1,2,4-oxadiazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(3-chloro-2-methylphenyl)-1,2-oxazol-3-yl]pyrrolidin-1-yl]-[5-methoxy-4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[3-(3-chloro-2-methoxyphenyl)-1H-1,2,4-triazol-5-yl]pyrrolidin-1-yl]-[4-chloro-5-methoxy-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S)-2-[5-(2-ethoxyphenyl)-1H-imidazol-2-yl]pyrrolidin-1-yl]-[4-methyl-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9493446: Orexin receptor antagonists which are [ortho bi-(hetero-)aryl]-[2-(meta bi-(hetero-)aryl)-pyrrolidin-1-yl]-methanone derivatives
[(2S,4R)-2-(5-chloro-4-methyl-1H-benzimidazol-2-yl)-4-methoxypyrrolidin-1-yl]-[5-methoxy-2-(triazol-2-yl)phenyl]methanone	IC50	1 nM	US-9732075: Benzimidazole-proline derivatives
(4-Bromo-biphenyl-2-yl)-[(S)-2-methyl-2-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-pyrrolidin-1-yl]-methanone	IC50	1 nM	US-9732075: Benzimidazole-proline derivatives

ChEMBL bioactivities

6100 potent at pChembl≥5 of 6100 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	Ki	0.06	nM	CHEMBL3597953
10.17	EC50	0.068	nM	CHEMBL5079059
10.00	IC50	0.1	nM	CHEMBL3906374
10.00	IC50	0.1	nM	CHEMBL5619450
9.90	Ki	0.1259	nM	CHEMBL1830963
9.89	EC50	0.13	nM	CHEMBL438925
9.80	Ki	0.1585	nM	CHEMBL1830961
9.70	Ki	0.2	nM	CHEMBL3260826
9.70	IC50	0.2	nM	CHEMBL5618671
9.68	IC50	0.21	nM	CHEMBL5618671
9.66	EC50	0.22	nM	CHEMBL438925
9.52	Ki	0.3	nM	SB-649868
9.52	Ki	0.3	nM	CHEMBL3260828
9.52	Ki	0.3	nM	CHEMBL3260835
9.52	Ki	0.3	nM	CHEMBL3260836
9.52	Ki	0.3	nM	CHEMBL3770503
9.52	IC50	0.3	nM	CHEMBL3941085
9.52	IC50	0.3	nM	CHEMBL3981385
9.50	Ki	0.3162	nM	SB-649868
9.41	Ki	0.39	nM	CHEMBL1083357
9.40	Ki	0.4	nM	CHEMBL3260833
9.40	Ki	0.3981	nM	CHEMBL3741853
9.40	IC50	0.4	nM	CHEMBL3946479
9.40	Ki	0.3981	nM	SUVOREXANT
9.40	IC50	0.4	nM	CHEMBL5619192
9.40	Ki	0.4	nM	CHEMBL1093725
9.40	Ki	0.4	nM	CHEMBL1172520
9.39	Ki	0.41	nM	CHEMBL3394847
9.39	EC50	0.41	nM	CHEMBL436915
9.36	Ki	0.437	nM	CHEMBL5993149
9.30	Ki	0.5	nM	CHEMBL2413365
9.30	Ki	0.5	nM	CHEMBL3260827
9.30	Ki	0.5	nM	CHEMBL3260831
9.30	IC50	0.5	nM	CHEMBL3945012
9.30	IC50	0.5	nM	CHEMBL3934350
9.30	IC50	0.5	nM	CHEMBL3917550
9.30	IC50	0.5	nM	CHEMBL6145318
9.30	IC50	0.5	nM	CHEMBL6167673
9.30	IC50	0.5	nM	CHEMBL6151110
9.28	EC50	0.52	nM	CHEMBL439541
9.26	Ki	0.55	nM	SUVOREXANT
9.25	Ki	0.56	nM	CHEMBL3235265
9.22	Ki	0.6	nM	SUVOREXANT
9.22	IC50	0.6	nM	CHEMBL5618824
9.22	IC50	0.6	nM	CHEMBL5619028
9.22	IC50	0.6	nM	CHEMBL5958771
9.22	IC50	0.6	nM	DARIDOREXANT
9.22	IC50	0.6	nM	CHEMBL6165886
9.22	Ki	0.6	nM	CHEMBL1171594
9.22	Ki	0.6	nM	CHEMBL1170178

PubChem BioAssay actives

1504 with measured affinity, of 2723 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
[(2S)-2-[2-(4-fluorophenoxy)ethyl]piperidin-1-yl]-(2-methyl-5-phenyl-1,3-thiazol-4-yl)methanone	1237020: Antagonist activity at orexin-1 receptor (unknown origin)	ki	0.0001	uM
(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-[[(2S,3R)-2-[[(2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-5-carbamimidamido-2-[[(2R)-2-[[(2R)-2-[[(2S)-3-carboxy-2-[[(2S)-1-[(2S)-4-methyl-2-[[(2S)-1-[(2S)-5-oxopyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-sulfanylpropanoyl]amino]-3-sulfanylpropanoyl]amino]pentanoyl]amino]-5-oxopentanoyl]amino]hexanoyl]amino]-3-hydroxybutanoyl]amino]-3-sulfanylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-sulfanylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-carboxybutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]acetyl]amino]propanoyl]amino]acetyl]amino]-4-oxobutanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]propanoyl]amino]propanoyl]amino]acetyl]amino]-3-methylpentanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoic acid	1827271: Agonist activity at human OX1R expressed in CHO-K1 cells by FLIPR calcium flux assay	ec50	0.0001	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[2-[(2-phenyltriazol-4-yl)methyl]pyrazolidin-1-yl]methanone	2130398: Antagonist activity at human OX1R overexpressing CHO cells by FLIPR assay	ic50	0.0001	uM
4-fluoro-N-[[(2S)-1-(2-phenylbenzoyl)piperidin-2-yl]methyl]benzamide	618062: Antagonist activity at recombinant human OX1R expressed in CHO cells by FLIPR calcium based functional assay	ki	0.0001	uM
(4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[2-[[(2S)-4-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S,3S)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-1,4-dioxobutan-2-yl]amino]-2-oxoethyl]amino]-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(1R,4S,7S,10S,13S,16R,21R,24S,31R)-7-(4-aminobutyl)-10-(3-amino-3-oxopropyl)-13-(3-carbamimidamidopropyl)-31-[[(2S)-3-carboxy-2-[[(2S)-1-[(2S)-4-methyl-2-[[(2S)-1-[(2S)-5-oxopyrrolidine-2-carbonyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]propanoyl]amino]-4-[(1R)-1-hydroxyethyl]-24-(hydroxymethyl)-3,6,9,12,15,23,26,32-octaoxo-18,19,28,29-tetrathia-2,5,8,11,14,22,25,33-octazabicyclo[14.10.7]tritriacontane-21-carbonyl]amino]-5-carbamimidamidopentanoyl]amino]-4-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-5-oxopentanoic acid	767535: Agonist activity at OX1 receptor (unknown origin) expressed in RD-HGA16 cells assessed as calcium mobilization by fluorescence assay	ec50	0.0001	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[2-[(1-phenylpyrazol-3-yl)methyl]pyrazolidin-1-yl]methanone	2130398: Antagonist activity at human OX1R overexpressing CHO cells by FLIPR assay	ic50	0.0002	uM
[(7R)-7-methyl-4-(5-methylfuro[2,3-d]pyrimidin-2-yl)-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0002	uM
[(2S)-2-[2-(2,4-difluorophenoxy)ethyl]piperidin-1-yl]-(2-phenylphenyl)methanone	618062: Antagonist activity at recombinant human OX1R expressed in CHO cells by FLIPR calcium based functional assay	ki	0.0002	uM
[(7R)-7-methyl-4-(5-methylthieno[2,3-d]pyrimidin-2-yl)-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0003	uM
[(7R)-4-(4-amino-5-methylthieno[2,3-d]pyrimidin-2-yl)-7-methyl-1,4-diazepan-1-yl]-[2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0003	uM
N-[[(2S)-1-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]piperidin-2-yl]methyl]-1-benzofuran-4-carboxamide	528164: Antagonist activity against human orexin 1 receptor expressed in CHO cells assessed as effect in calcium mobilization by FLIPR assay	ki	0.0003	uM
[(2R,5R)-5-[(4-fluoro-3-methylphenoxy)methyl]-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1279994: Binding affinity to OX1R (unknown origin)	ki	0.0003	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[[3-(triazol-2-yl)phenyl]methyl]piperidin-1-yl]methanone	2100182: Antagonist activity at human OX1R expressed in CHO cells preincubated for 120 mins followed by orexin-A addition by FLIPR assay	ic50	0.0003	uM
[(7R)-4-(4-amino-5-methylthieno[2,3-d]pyrimidin-2-yl)-7-methyl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0003	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[2-[(1-phenyl-1,2,4-triazol-3-yl)methyl]pyrazolidin-1-yl]methanone	2130398: Antagonist activity at human OX1R overexpressing CHO cells by FLIPR assay	ic50	0.0004	uM
Suvorexant	1582239: Displacement of [3H]4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide from human wild-type OX1 receptor expressed in baculovirus infected Sf21 insect cell membranes measured after 90 mins by liquid scintillation counting method	ki	0.0004	uM
(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[2-[[(2S)-2-[[2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]acetyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2S)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0004	uM
[(2R,5R)-5-(4-methoxyisoquinolin-1-yl)oxy-2-methylpiperidin-1-yl]-[2-(triazol-2-yl)phenyl]methanone	1190415: Antagonist activity at human OX1R by radioligand displacement assay	ki	0.0004	uM
[(7R)-7-methyl-4-quinazolin-2-yl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	482633: Displacement of 3H-N-(biphenyl-2-yl)-1-(2-(1-methyl-1H-benzo[d]imidazol-2-ylthio)acetyl)pyrrolidine-2-carboxamide from human OX1R expressed in CHO cells after 3 hrs by scintillation counting	ki	0.0004	uM
[5-chloro-2-(triazol-2-yl)phenyl]-[6-(6-fluoroquinazolin-2-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl]methanone	474966: Binding affinity to OX1 receptor by radioligand displacement assay	ki	0.0004	uM
[5-chloro-2-(triazol-2-yl)phenyl]-[(1R,5R)-6-(6-fluoroquinazolin-2-yl)-3,6-diazabicyclo[3.2.1]octan-3-yl]methanone	489199: Binding affinity to OX1R	ki	0.0004	uM
[(7R)-4-(4-amino-6-methylthieno[2,3-d]pyrimidin-2-yl)-7-methyl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0004	uM
[(7R)-4-(5,6-dimethylfuro[2,3-d]pyrimidin-2-yl)-7-methyl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0005	uM
(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]propanoyl]amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2S)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0005	uM
[(2S,3R)-3-(isoquinolin-1-yloxymethyl)-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	765089: Binding affinity to orexin receptor 1 (unknown origin)	ki	0.0005	uM
[(7R)-4-(4-aminothieno[2,3-d]pyrimidin-2-yl)-7-methyl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0005	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[2-[(3-pyrimidin-2-ylphenyl)methyl]pyrazolidin-1-yl]methanone	2130398: Antagonist activity at human OX1R overexpressing CHO cells by FLIPR assay	ic50	0.0006	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[2-[(3-phenyl-1H-pyrazol-5-yl)methyl]pyrazolidin-1-yl]methanone	2130398: Antagonist activity at human OX1R overexpressing CHO cells by FLIPR assay	ic50	0.0006	uM
[(2R,5R)-5-[(5-fluoro-2-pyridinyl)oxymethyl]-2-methylpiperidin-1-yl]-(5-methyl-2-pyrimidin-2-ylphenyl)methanone	1582239: Displacement of [3H]4-(2,6-Difluoro-4-methoxybenzyl)-2-(5,6-dimethoxypyridin-3-yl)-2H-1,2,4-benzothiadiazin-3(4H)-one 1,1-dioxide from human wild-type OX1 receptor expressed in baculovirus infected Sf21 insect cell membranes measured after 90 mins by liquid scintillation counting method	ki	0.0006	uM
(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2R)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2S)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0006	uM
[3-(7-fluoroquinazolin-2-yl)-3,9-diazabicyclo[4.2.1]nonan-9-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	489199: Binding affinity to OX1R	ki	0.0006	uM
[(1R,5R)-2-(7-fluoroquinazolin-2-yl)-2,6-diazabicyclo[3.2.2]nonan-6-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	489199: Binding affinity to OX1R	ki	0.0006	uM
[(2R,5S)-5-[2-[3-(hydroxymethyl)phenyl]ethynyl]-2-methylpiperidin-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1124759: Binding affinity to human OX1 receptor in cell membrane by in vitro radioligand binding assay	ki	0.0006	uM
[5-methyl-2-(triazol-2-yl)phenyl]-(6-quinazolin-2-yl-3,6-diazabicyclo[3.2.1]octan-3-yl)methanone	474966: Binding affinity to OX1 receptor by radioligand displacement assay	ki	0.0007	uM
(2S)-1-[2-(1,5-dimethylbenzimidazol-2-yl)sulfanylacetyl]-N-(2-pyrrol-1-ylphenyl)pyrrolidine-2-carboxamide	321313: Displacement of 3H-1-[2-(1-methyl-1H-benzoimidazol-2-ylsulfanyl)-acetyl]-pyrrolidine-2-carboxylic acid biphenyl-2-ylamide from human OX1R expressed in CHO cells	ki	0.0007	uM
[5-methyl-2-(triazol-2-yl)phenyl]-[(2S)-2-[[3-(triazol-2-yl)phenyl]methyl]pyrrolidin-1-yl]methanone	2100182: Antagonist activity at human OX1R expressed in CHO cells preincubated for 120 mins followed by orexin-A addition by FLIPR assay	ic50	0.0007	uM
[(7R)-4-(4-amino-6-methylthieno[2,3-d]pyrimidin-2-yl)-7-methyl-1,4-diazepan-1-yl]-[2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0007	uM
[2-methyl-5-(3-methylphenyl)-1,3-thiazol-4-yl]-[(2S)-2-[[3-(triazol-2-yl)phenyl]methyl]pyrrolidin-1-yl]methanone	2100182: Antagonist activity at human OX1R expressed in CHO cells preincubated for 120 mins followed by orexin-A addition by FLIPR assay	ic50	0.0008	uM
[(3aS,9bR)-7-fluoro-1-[(3-pyrimidin-2-ylphenyl)methyl]-3,3a,4,9b-tetrahydrochromeno[4,3-c]pyrazol-2-yl]-(2,5-dimethylpyrazol-3-yl)methanone	2130398: Antagonist activity at human OX1R overexpressing CHO cells by FLIPR assay	ic50	0.0008	uM
[(7R)-4-(1,3-dimethylpyrazolo[3,4-d]pyrimidin-6-yl)-7-methyl-1,4-diazepan-1-yl]-[5-methyl-2-(triazol-2-yl)phenyl]methanone	1139799: Displacement of [3H]radioligand from human orexin-1 receptor expressed in CHO cells after 3 hrs by scintillation counting analysis	ki	0.0008	uM
[(7R)-7-methyl-4-(5,6,7,8-tetrahydroquinazolin-2-yl)-1,4-diazepan-1-yl]-[2-(triazol-2-yl)phenyl]methanone	482633: Displacement of 3H-N-(biphenyl-2-yl)-1-(2-(1-methyl-1H-benzo[d]imidazol-2-ylthio)acetyl)pyrrolidine-2-carboxamide from human OX1R expressed in CHO cells after 3 hrs by scintillation counting	ki	0.0008	uM
(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2S)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0008	uM
(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2S)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0008	uM
(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2R)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0008	uM
(2S)-2-[[2-[[(2S)-2-[[(2R)-2-[[(2R)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-hydroxybutanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]propanoyl]amino]propanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-4-oxobutanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]propanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]acetyl]amino]-N-[(2S)-1-[[2-[(2S)-2-[(2S)-2-[[2-[[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]carbamoyl]pyrrolidine-1-carbonyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-4-methyl-1-oxopentan-2-yl]pentanediamide	256556: Agonist activity against human orexin 1 receptor; EC50; nM	ec50	0.0008	uM
N-[[(2S,3R)-3-methyl-1-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)piperidin-2-yl]methyl]-1-benzofuran-4-carboxamide	661283: Antagonist activity at OX1 receptor expressed in CHO cells assessed as inhibition of OXA-stimulated intracellular calcium mobilization after 30 mins by FLIPR assay	ic50	0.0008	uM
N-[[(2S,6S)-1-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-6-methylpiperidin-2-yl]methyl]-1-benzofuran-4-carboxamide	661283: Antagonist activity at OX1 receptor expressed in CHO cells assessed as inhibition of OXA-stimulated intracellular calcium mobilization after 30 mins by FLIPR assay	ic50	0.0008	uM
N-ethyl-N-[(2S)-1-[5-(4-fluorophenyl)tetrazol-2-yl]propan-2-yl]-5-methyl-2-(triazol-2-yl)benzamide	1463501: Antagonist activity at human OX1R expressed in CHO cells assessed as reduction in [Ala6,12]orexin-A-induced intracellular Ca2+ mobilization incubated for 30 mins by Fluo-4AM dye based fluorescence assay	ic50	0.0008	uM
N-ethyl-N-[(2S)-1-[4-(5-fluoro-2-pyridinyl)pyrazol-1-yl]propan-2-yl]-5-methyl-2-(triazol-2-yl)benzamide	1463501: Antagonist activity at human OX1R expressed in CHO cells assessed as reduction in [Ala6,12]orexin-A-induced intracellular Ca2+ mobilization incubated for 30 mins by Fluo-4AM dye based fluorescence assay	ic50	0.0008	uM
[(3S)-4,4-difluoro-3-quinolin-2-yloxypiperidin-1-yl]-imidazo[1,5-a]pyridin-8-ylmethanone	1328738: Binding affinity to OX1 receptor (unknown origin)	kd	0.0009	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	2
aminomethylphosphonic acid (AMPA)	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
terbufos	increases methylation	1
1-(2-methylbenzoxazol-6-yl)-3-(1,5)naphthyridin-4-yl urea	affects binding, decreases activity	1
Arsenic Trioxide	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Cadmium	decreases expression, increases abundance	1
Cannabidiol	affects binding, decreases activity	1
Copper	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
2,4-Dichlorophenoxyacetic Acid	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

ChEMBL screening assays

280 unique, capped per target: 154 binding, 126 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3291793	Functional	Antagonist activity at CB1-OX1 heterodimer (unknown origin) expressed in RD-HGA16 cells assessed as inhibition of CP55940-induced calcium mobilization by fluorometric imaging plate reader analysis	Toward the Development of Bivalent Ligand Probes of Cannabinoid CB1 and Orexin OX1 Receptor Heterodimers. — ACS Med Chem Lett
CHEMBL1007895	Binding	Binding affinity to OX1 receptor	Biomedical application of orexin/hypocretin receptor ligands in neuroscience. — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 spontaneously immortalized cell line, 1 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_H487	CHO-K1/OX1	Spontaneously immortalized cell line	Female
CVCL_KX81	PathHunter CHO-K1 HCRTR1 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_LA49	PathHunter U2OS HCRTR1 Total GPCR Internalization	Cancer cell line	Female
CVCL_LB57	GeneBLAzer HCRTR1-NFAT-bla CHO-K1	Spontaneously immortalized cell line	Female
CVCL_RL73	GT1-7-OX1	Transformed cell line

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy