ADORA1

Summary

ADORA1 (adenosine A1 receptor, HGNC:262) is a protein-coding gene on chromosome 1q32.1, encoding Adenosine receptor A1 (P30542). Receptor for adenosine.

The protein encoded by this gene is an adenosine receptor that belongs to the G-protein coupled receptor 1 family. There are 3 types of adenosine receptors, each with a specific pattern of ligand binding and tissue distribution, and together they regulate a diverse set of physiologic functions. The type A1 receptors inhibit adenylyl cyclase, and play a role in the fertilization process. Animal studies also suggest a role for A1 receptors in kidney function and ethanol intoxication. Transcript variants with alternative splicing in the 5’ UTR have been found for this gene.

Source: NCBI Gene 134 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 51 total
• Druggable target: yes — 85 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000674

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:262
Approved symbol	ADORA1
Name	adenosine A1 receptor
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	RDC7
Ensembl gene	ENSG00000163485
Ensembl biotype	protein_coding
OMIM	102775
Entrez	134

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 6 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000309502, ENST00000337894, ENST00000367235, ENST00000367236, ENST00000464019, ENST00000467253, ENST00000472535, ENST00000867101, ENST00000867102

RefSeq mRNA: 4 — MANE Select: NM_000674 NM_000674, NM_001048230, NM_001365065, NM_001365066

CCDS: CCDS1434

Canonical transcript exons

ENST00000337894 — 4 exons

Exon	Start	End
ENSE00001075161	203128278	203128432
ENSE00003844237	203127726	203127928
ENSE00003891837	203128785	203129182
ENSE00003894279	203165261	203167405

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 94.67.

FANTOM5 (CAGE): breadth broad, TPM avg 5.9551 / max 232.1216, expressed in 831 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7844	4.0000	613
7839	0.9721	409
7840	0.8057	270
7845	0.0531	24
7843	0.0436	17
7841	0.0428	20
7842	0.0378	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
inferior vagus X ganglion	UBERON:0005363	94.67	gold quality
prefrontal cortex	UBERON:0000451	94.04	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.32	gold quality
lateral nuclear group of thalamus	UBERON:0002736	93.20	gold quality
Brodmann (1909) area 10	UBERON:0013541	93.08	gold quality
putamen	UBERON:0001874	92.67	gold quality
pons	UBERON:0000988	92.60	gold quality
amygdala	UBERON:0001876	92.52	gold quality
spinal cord	UBERON:0002240	92.45	gold quality
ventral tegmental area	UBERON:0002691	92.19	gold quality
right frontal lobe	UBERON:0002810	92.17	gold quality
vena cava	UBERON:0004087	92.07	silver quality
dorsal plus ventral thalamus	UBERON:0001897	91.88	gold quality
middle frontal gyrus	UBERON:0002702	91.75	gold quality
nucleus accumbens	UBERON:0001882	91.51	gold quality
cingulate cortex	UBERON:0003027	91.50	gold quality
caudate nucleus	UBERON:0001873	91.49	gold quality
midbrain	UBERON:0001891	91.48	gold quality
anterior cingulate cortex	UBERON:0009835	91.45	gold quality
frontal pole	UBERON:0002795	91.32	gold quality
frontal cortex	UBERON:0001870	91.30	gold quality
substantia nigra	UBERON:0002038	91.28	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.98	gold quality
subthalamic nucleus	UBERON:0001906	90.90	gold quality
superior vestibular nucleus	UBERON:0007227	90.56	gold quality
neocortex	UBERON:0001950	90.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.47	gold quality
telencephalon	UBERON:0001893	90.23	gold quality
lateral globus pallidus	UBERON:0002476	90.05	gold quality
tendon of biceps brachii	UBERON:0008188	89.94	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, ESR1, ESR2, GATA4, NFKB1, NKX2-5, RELA, TCF3, ZMYND8

miRNA regulators (miRDB)

54 targeting ADORA1, 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-4283	100.00	66.42	2097
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4673	100.00	66.64	1490
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-4645-5P	99.98	65.81	1284
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-532-3P	99.34	65.76	1195
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-4279	99.19	66.70	2437
HSA-MIR-6852-5P	99.17	66.69	2073

Literature-anchored findings (GeneRIF, showing 40)

• Human A1 adenosine receptor overexpressed in adipose tissue of transgenic mice protects them from obesity-related insulin resistance. (PMID:11703426)
• A(1)- and A(2a)-adenosine receptor activation protects HK-2 proximal kidney tubule cells against H(2)O(2)-induced injury (PMID:11934694)
• Putative sites for palmitoylation and phosphorylation within the A1-subtype adenosine receptor’s carboxyl terminus do not play a key role in controlling agonist-stimulated changes in subcellular trafficking of the receptor. (PMID:12475223)
• the membrane-proximal carboxyl terminus of the A1 adenosine receptor in receptor folding and G protein coupling (PMID:12764156)
• data suggest that protein kinase C mu plays an important role in the ability of the adenosine A(1) receptor to signal to the nucleus (PMID:12812995)
• building of a human A(1) adenosine receptor (hA(1)AR) model, based on the X-ray crystal structure of bovine rhodopsin, and its use as a basis for the investigation of some important structural characteristics of the receptor (PMID:14997566)
• adenosine-related gene variants do not appear to alter susceptibility to the disease in this group of essential hypertensives. (PMID:15257174)
• G16-mediated activation of nuclear factor kappaB by the adenosine A1 receptor requires c-Src, protein kinase C, and ERK signaling (PMID:15485865)
• Stimulation of adenosine A(1) receptors on HBSMC rapidly mobilizes intracellular calcium stores by a mechanism dependent on PTX-sensitive G proteins, and IP(3) signaling. (PMID:16709961)
• Robust constitutive myocardial A1-AR overexpression induces a dilated cardiomyopathy, whereas delaying A1-AR expression until adulthood ameliorated but did not eliminate development of cardiac pathology. (PMID:17088462)
• The binding sites of ADORA1 reengineered for orthogonal recognition by tailored nucleosides were probed. (PMID:17542617)
• Genetic variants in the adenosine A1/A3 receptor genes may predict the heart’s response to ischemia or injury and might also influence an individual’s response to adenosine therapy. (PMID:17728764)
• A1 AR-selective agonist CPA stimulated a 1.7-fold increase in VEGF release from the mononuclear cells (PMID:17901362)
• Adenosine A1 receptor-adenylyl cyclase transduction pathway is specifically up-regulated and sensitized in frontal cortex brain in Pick’s disease. (PMID:18052973)
• Adenosine A1 receptor gene expression is proportional to the extent of stent-induced neointimal proliferation. (PMID:18281812)
• With 300 MBq of injected (18)F-CPFPX a subject receives an effective dose (ICRP 60) of 5.3 mSv. (PMID:18373090)
• The interaction between A(1) and P2Y(1) receptors may play an important role in the purinergic signaling cascade in astrocytes (PMID:18500760)
• Human ADA, apart from reducing the adenosine concentration and thus preventing A(1)R desensitization, binds to A(1)R behaving as an allosteric effector that markedly enhances agonist affinity and increases receptor functionality. (PMID:18680557)
• A(1) receptors mediate direct modulating actions on human colonic motility on smooth muscle (PMID:19019012)
• Genetic polymorphisms of ADORA1 and ADORA2A were significantly associated with aspirin-intolerant-asthma in a Korean population. (PMID:19019667)
• Caffeine modulates TNF-alpha production by cord blood monocytes: the role of adenosine receptors. (PMID:19047957)
• The ability to increase synchronized slow-wave activity from waking to slow-wave sleep is significantly attenuated by the loss of adenosine A1 receptor expression in AdoA1R(f/f) floxed mice. (PMID:19193874)
• endogenous activation of A(1)-AR contributes to the early development of renal ischaemia/reperfusion injury. (PMID:19207864)
• Our study provides strong evidence of the essential role of the highly conserved Trp132 in TM4 of adenosine receptors. (PMID:19558453)
• Data suggest that adenosine A(1)receptor-mediated EGF receptor transactivation confers a neuroprotective effect in primary cortical neurons. (PMID:19574994)
• Data suggest that adenosine receptor modulation may be useful for refining the use of chemotherapeutic drugs to treat human cancer more effectively. (PMID:19794965)
• ADORA1 polymorphisms may represent good candidate markers for schizophrenia research and ADORA1 may be involved in the pathophysiological mechanisms of schizophrenia in Japanese populations (PMID:19820430)
• Adenosine, thus, suppresses CW2 human colonic cancer growth by inducing apoptosis as mediated via A(1) adenosine receptors. (PMID:19822392)
• Studies indicate that adenosine mediates its actions by means of activation of specifiic G protein-coupled receptors, for which 4 subbtypes: A1R, A2AR, A2BR and A3R have been identified so far. (PMID:19883624)
• Report cardio-renal effects of the A1 adenosine receptor antagonist SLV320 in patients with heart failure. (PMID:19919976)
• Findings suggest that the adenosine A1 (and possibly coordinated with A2a) receptors contribute to dendritic cell differentiation and survival. (PMID:20085598)
• Report fluorescence-based techniques, and in particular the development of fluorescent ligands, so study pharmacology of the adenosine A1 receptor. (PMID:20105183)
• results suggest that adenosine-mediated signaling in the heart requires a balance between A(1)- and A(2A)-receptors (PMID:20354569)
• LUF5834 represents a novel high affinity radioligand for the A(1)R and may prove a useful tool to provide estimates of inverse agonist efficacy at this receptor. (PMID:20599769)
• report implicating genetic variability in the A1AR with post-traumatic seizures. (PMID:20609566)
• Inhibition of human mast cell activation would be a mechanism for A AR antagonists, but not A(2B) AR antagonists. (PMID:21506953)
• ADORA1 was expressed in nucleus, perinucleus and cytoplasm of retinal pigment epithelium. (PMID:21542986)
• Adenosine receptor expression and activation during the differentiation of mesenchymal stem cell to osteoblasts and adipocytes, was investigated. (PMID:21590734)
• two genes involved in cardiovascular diseases, ADORA1 and PTGDS, were differentially up-regulated in epicardial adipose tissue compared to mediastinal and subcutaneous adipose tissue (PMID:21603615)
• Data suggest that adenosine deficiency may be relevant to human epilepsy and that a ketogenic diet can reduce seizures by increasing adenosine A1 receptor-mediated inhibition. (PMID:21701065)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	adora1a	ENSDARG00000070056
danio_rerio	adora1b	ENSDARG00000075694
mus_musculus	Adora1	ENSMUSG00000042429
rattus_norvegicus	Adora1	ENSRNOG00000084234
drosophila_melanogaster	AdoR	FBGN0039747

Paralogs (3): ADORA2A (ENSG00000128271), ADORA2B (ENSG00000170425), ADORA3 (ENSG00000282608)

Protein

Protein identifiers

Adenosine receptor A1 — P30542 (reviewed: P30542)

All UniProt accessions (1): P30542

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for adenosine. The activity of this receptor is mediated by G proteins such as GNAI2 which inhibit adenylyl cyclase.

Subunit / interactions. Interacts with GNAI2.

Subcellular location. Cell membrane.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P30542-1	1	yes
P30542-2	2

RefSeq proteins (4): NP_000665, NP_001041695, NP_001351994, NP_001351995 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR001068	Adeno_A1_rcpt	Family
IPR001634	Adenosn_rcpt	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain

Pfam: PF00001

UniProt features (48 total): helix 16, topological domain 8, transmembrane region 7, sequence variant 6, disulfide bond 2, splice variant 2, strand 2, chain 1, lipid moiety-binding region 1, glycosylation site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5UEN	X-RAY DIFFRACTION	3.2
7LD3	ELECTRON MICROSCOPY	3.2
7LD4	ELECTRON MICROSCOPY	3.3
5N2S	X-RAY DIFFRACTION	3.3
6D9H	ELECTRON MICROSCOPY	3.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30542-F1	92.60	0.84

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 (1): 309

Disulfide bonds (2): 80–169, 260–263

Glycosylation sites (1): 159

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-417973	Adenosine P1 receptors
R-HSA-418594	G alpha (i) signalling events
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373076	Class A/1 (Rhodopsin-like receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-418038	Nucleotide-like (purinergic) receptors
R-HSA-500792	GPCR ligand binding

MSigDB gene sets: 381 (showing top): GOBP_CIRCADIAN_RHYTHM, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_ACYLGLYCEROL_HOMEOSTASIS, ELVIDGE_HYPOXIA_DN, MODULE_92, GOBP_G_PROTEIN_COUPLED_PURINERGIC_RECEPTOR_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_GLUTAMATE_SECRETION, GOBP_G_PROTEIN_COUPLED_PURINERGIC_NUCLEOTIDE_RECEPTOR_SIGNALING_PATHWAY, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_COGNITION, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_BEHAVIOR, GOBP_REGULATION_OF_BLOOD_PRESSURE

GO Biological Process (56): temperature homeostasis (GO:0001659), response to hypoxia (GO:0001666), regulation of respiratory gaseous exchange by nervous system process (GO:0002087), negative regulation of acute inflammatory response (GO:0002674), negative regulation of leukocyte migration (GO:0002686), positive regulation of peptide secretion (GO:0002793), positive regulation of systemic arterial blood pressure (GO:0003084), negative regulation of systemic arterial blood pressure (GO:0003085), regulation of glomerular filtration (GO:0003093), protein targeting to membrane (GO:0006612), phagocytosis (GO:0006909), inflammatory response (GO:0006954), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), cell-cell signaling (GO:0007267), nervous system development (GO:0007399), negative regulation of cell population proliferation (GO:0008285), negative regulation of glutamate secretion (GO:0014050), response to purine-containing compound (GO:0014074), lipid catabolic process (GO:0016042), negative regulation of synaptic transmission, GABAergic (GO:0032229), positive regulation of nucleoside transport (GO:0032244), negative regulation of neurotrophin production (GO:0032900), positive regulation of dephosphorylation (GO:0035306), G protein-coupled purinergic nucleotide receptor signaling pathway (GO:0035589), vasodilation (GO:0042311), negative regulation of circadian sleep/wake cycle, non-REM sleep (GO:0042323), negative regulation of apoptotic process (GO:0043066), positive regulation of potassium ion transport (GO:0043268), positive regulation of MAPK cascade (GO:0043410), negative regulation of hormone secretion (GO:0046888), cognition (GO:0050890), leukocyte migration (GO:0050900), detection of temperature stimulus involved in sensory perception of pain (GO:0050965), negative regulation of lipid catabolic process (GO:0050995), positive regulation of lipid catabolic process (GO:0050996), regulation of sensory perception of pain (GO:0051930), negative regulation of synaptic transmission, glutamatergic (GO:0051967), fatty acid homeostasis (GO:0055089)

GO Molecular Function (10): G protein-coupled adenosine receptor activity (GO:0001609), G protein-coupled receptor binding (GO:0001664), purine nucleoside binding (GO:0001883), heat shock protein binding (GO:0031072), G-protein beta/gamma-subunit complex binding (GO:0031683), heterotrimeric G-protein binding (GO:0032795), protein heterodimerization activity (GO:0046982), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515), protein-containing complex binding (GO:0044877)

GO Cellular Component (16): plasma membrane (GO:0005886), cilium (GO:0005929), basolateral plasma membrane (GO:0016323), dendrite (GO:0030425), axolemma (GO:0030673), asymmetric synapse (GO:0032279), presynaptic membrane (GO:0042734), neuronal cell body (GO:0043025), terminal bouton (GO:0043195), dendritic spine (GO:0043197), calyx of Held (GO:0044305), synapse (GO:0045202), postsynaptic membrane (GO:0045211), presynaptic active zone (GO:0048786), membrane (GO:0016020), cell body (GO:0044297)

Reactome top-level categories

Rollup of top-6 pathways:

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
presynapse	3
cellular anatomical structure	3
regulation of systemic arterial blood pressure	2
cell communication	2
signaling	2
G protein-coupled receptor activity	2
protein-containing complex binding	2
binding	2
synaptic membrane	2
axon terminus	2
postsynapse	2
multicellular organismal-level homeostasis	1
response to stress	1
response to decreased oxygen levels	1
respiratory gaseous exchange by respiratory system	1
regulation of respiratory system process	1
nervous system process	1
acute inflammatory response	1
regulation of acute inflammatory response	1
negative regulation of inflammatory response	1
negative regulation of immune system process	1
regulation of leukocyte migration	1
negative regulation of cell migration	1
leukocyte migration	1
peptide secretion	1
regulation of peptide secretion	1
positive regulation of secretion	1
positive regulation of blood pressure	1
negative regulation of blood pressure	1
glomerular filtration	1
regulation of renal system process	1
protein targeting	1
establishment of protein localization to membrane	1
endocytosis	1
defense response	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1

Protein interactions and networks

STRING

1462 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADORA1	SLC29A1	Q99808	880
ADORA1	ADA	P00813	792
ADORA1	NT5E	P21589	727
ADORA1	P2RY1	P47900	689
ADORA1	SLC29A2	Q14542	689
ADORA1	VIPR1	P32241	678
ADORA1	ENTPD1	P49961	665
ADORA1	LTBP3	Q9NS15	648
ADORA1	ADORA2A	P29274	647
ADORA1	LTBP2	Q14767	639
ADORA1	ADK	P55263	612
ADORA1	LTBP1	P22064	606
ADORA1	DRD1	P21728	537
ADORA1	DRD2	P14416	535
ADORA1	GNAO1	P09471	527

IntAct

32 interactions, top by confidence:

A	B	Type	Score
ADRB1	ADORA1	psi-mi:“MI:0915”(physical association)	0.610
ADRB2	ADORA1	psi-mi:“MI:0915”(physical association)	0.610
ADORA1	ADRB2	psi-mi:“MI:0914”(association)	0.610
ADORA2A	ADORA1	psi-mi:“MI:0915”(physical association)	0.520
ADORA1	ADORA2A	psi-mi:“MI:0915”(physical association)	0.520
ADORA2A	ADORA1	psi-mi:“MI:2364”(proximity)	0.520
ADORA1	ADORA2A	psi-mi:“MI:0403”(colocalization)	0.520
TSHR	ADORA1	psi-mi:“MI:0915”(physical association)	0.510
ADORA1	TSHR	psi-mi:“MI:0915”(physical association)	0.510
ADORA1	RAMP2	psi-mi:“MI:0915”(physical association)	0.470
RAMP2	ADORA1	psi-mi:“MI:0915”(physical association)	0.470
ADORA1	RAMP2	psi-mi:“MI:2364”(proximity)	0.470
ADORA1	DRD1	psi-mi:“MI:0915”(physical association)	0.460
ADORA1	DRD1	psi-mi:“MI:0403”(colocalization)	0.460
	ADORA1	psi-mi:“MI:0915”(physical association)	0.400
ADORA1	RAMP1	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	ADORA1	psi-mi:“MI:0915”(physical association)	0.400
ADORA1	RAMP3	psi-mi:“MI:0915”(physical association)	0.400
RAMP1	ADORA1	psi-mi:“MI:0915”(physical association)	0.400
ADORA1	SNF8	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (17): EGFR (Affinity Capture-Western), DRD1 (Affinity Capture-Western), ADORA1 (Co-localization), TSHR (Affinity Capture-Western), ADORA1 (Two-hybrid), ADORA1 (Affinity Capture-RNA), ADORA1 (Affinity Capture-Western), GNAI2 (Affinity Capture-Western), ADORA1 (Affinity Capture-Western), UBAC2 (Affinity Capture-MS), PELI3 (Affinity Capture-MS), SORBS3 (Affinity Capture-MS), BRI3BP (Affinity Capture-MS), UFD1L (Affinity Capture-MS), NPLOC4 (Affinity Capture-MS)

ESM2 similar proteins: A5A4K9, A5A4L1, B2ZI34, F1MV99, O08725, O08786, O42329, O43193, O62709, O97772, P11616, P21451, P21729, P24053, P25099, P26684, P28088, P28190, P28646, P30542, P30550, P30551, P30872, P30873, P32238, P33534, P34970, P34975, P35342, P41144, P41145, P47745, P47751, P48302, P52500, P60893, P60894, P60895, Q2KIP6, Q49LX5

Diamond homologs: B2RPY5, B3DM66, O02664, O13076, O19014, O19032, O19091, O77408, O77621, O77713, O77721, P08908, P0DMS8, P16395, P18089, P18130, P19327, P21917, P22270, P30542, P30552, P32229, P32239, P32250, P34970, P43657, P46627, P49220, P49684, P97718, Q09388, Q0EAB6, Q18904, Q24563, Q25321, Q25322, Q25414, Q2YDN1, Q4G072, Q4LBB6

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
ADORA1	“up-regulates activity”	GNAI1	binding
ADORA1	“up-regulates activity”	GNAI3	binding
ADORA1	“up-regulates activity”	GNAO1	binding
ADORA1	“up-regulates activity”	GNAZ	binding
adenosine	“up-regulates activity”	ADORA1	“chemical activation”
ZMYND8	“up-regulates quantity by expression”	ADORA1	“transcriptional regulation”
adenosine	“up-regulates activity”	ADORA1	binding
ADA	“up-regulates activity”	ADORA1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 10 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
G alpha (s) signalling events	8	58.6×	2e-12

GO biological processes:

GO term	Partners	Fold	FDR
adenylate cyclase-activating G protein-coupled receptor signaling pathway	7	79.2×	8e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	8
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1273 predictions. Top by Δscore:

Variant	Effect	Δscore
1:203093258:C:G	acceptor_gain	0.9900
1:203165255:CCCCA:C	acceptor_loss	0.9900
1:203165256:CCCA:C	acceptor_loss	0.9900
1:203165257:CCA:C	acceptor_loss	0.9900
1:203165258:CAG:C	acceptor_loss	0.9900
1:203165259:AGG:A	acceptor_loss	0.9900
1:203090733:GG:G	donor_gain	0.9800
1:203090734:GG:G	donor_gain	0.9800
1:203129180:CCGG:C	donor_loss	0.9800
1:203129182:GG:G	donor_loss	0.9800
1:203129183:GTG:G	donor_loss	0.9800
1:203129184:TGAGT:T	donor_loss	0.9800
1:203129185:GAGTC:G	donor_loss	0.9800
1:203129186:A:AA	donor_loss	0.9800
1:203129187:G:A	donor_loss	0.9800
1:203165259:A:AG	acceptor_gain	0.9800
1:203165260:G:GG	acceptor_gain	0.9800
1:203093260:T:G	acceptor_gain	0.9600
1:203129183:G:GG	donor_gain	0.9600
1:203150781:G:GA	donor_gain	0.9600
1:203090735:G:GG	donor_gain	0.9500
1:203150780:T:TA	donor_gain	0.9500
1:203165151:G:GT	donor_gain	0.9400
1:203165158:A:T	donor_gain	0.9300
1:203165259:AG:A	acceptor_gain	0.9300
1:203165260:GG:G	acceptor_gain	0.9300
1:203090731:AAGG:A	donor_loss	0.9200
1:203090733:GGGTA:G	donor_loss	0.9200
1:203090735:GTA:G	donor_loss	0.9200
1:203090736:T:A	donor_loss	0.9200

AlphaMissense

2131 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:203128922:C:A	N27K	0.999
1:203128922:C:G	N27K	0.999
1:203129004:G:C	D55H	0.999
1:203129005:A:T	D55V	0.999
1:203165431:T:G	F171C	0.999
1:203165646:T:C	F243L	0.999
1:203165648:T:A	F243L	0.999
1:203165648:T:G	F243L	0.999
1:203129005:A:C	D55A	0.998
1:203129005:A:G	D55G	0.998
1:203129006:T:A	D55E	0.998
1:203129006:T:G	D55E	0.998
1:203129016:G:C	G59R	0.998
1:203129155:G:C	R105P	0.998
1:203165334:G:A	G139R	0.998
1:203165334:G:C	G139R	0.998
1:203165424:T:A	C169S	0.998
1:203165424:T:C	C169R	0.998
1:203165425:G:C	C169S	0.998
1:203165430:T:C	F171L	0.998
1:203165432:C:A	F171L	0.998
1:203165432:C:G	F171L	0.998
1:203165658:T:A	W247R	0.998
1:203165658:T:C	W247R	0.998
1:203128917:G:A	G26R	0.997
1:203128917:G:C	G26R	0.997
1:203128993:T:C	L51P	0.997
1:203129004:G:T	D55Y	0.997
1:203165313:T:A	W132R	0.997
1:203165313:T:C	W132R	0.997

dbSNP variants (sampled 300 via entrez): RS1000025047 (1:203164092 G>A), RS1000056875 (1:203141682 G>C), RS1000076697 (1:203135412 A>G), RS1000077346 (1:203164432 C>G,T), RS1000208680 (1:203145112 C>G,T), RS1000231481 (1:203159101 C>A), RS1000247064 (1:203152337 G>C), RS1000383311 (1:203152801 G>A,T), RS1000385185 (1:203151138 A>G,T), RS1000450230 (1:203140415 G>A,T), RS1000488657 (1:203146558 G>A), RS1000499109 (1:203158616 A>G), RS1000596448 (1:203140244 G>A), RS1000608046 (1:203140666 A>G), RS1000718476 (1:203152667 T>C)

Disease associations

OMIM: gene MIM:102775 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002595_27	Clozapine-induced agranulocytosis	9.000000e-06
GCST003987_20	Asthma	1.000000e-08
GCST006624_22	Systolic blood pressure	2.000000e-10
GCST007798_15	Asthma	9.000000e-11
GCST007800_75	Asthma (childhood onset)	5.000000e-21
GCST007995_28	Asthma (childhood onset)	1.000000e-09
GCST008916_58	Asthma	1.000000e-11
GCST009720_89	Asthma	4.000000e-12
GCST009798_35	Asthma	8.000000e-12
GCST010042_105	Asthma	1.000000e-11
GCST010043_90	Asthma	7.000000e-16
GCST90020025_1238	Waist-to-hip ratio adjusted for BMI	1.000000e-08
GCST90020027_1926	Waist-hip index	6.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (8): CHEMBL2095195 (SELECTIVITY GROUP), CHEMBL2096679 (SELECTIVITY GROUP), CHEMBL2096908 (SELECTIVITY GROUP), CHEMBL2096982 (SELECTIVITY GROUP), CHEMBL2111329 (PROTEIN FAMILY), CHEMBL226 (SINGLE PROTEIN), CHEMBL3885512 (PROTEIN COMPLEX), CHEMBL5169080 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

85 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 712,643 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL104	CLOTRIMAZOLE	4	56,325
CHEMBL1077	BROMFENAC	4	12,495
CHEMBL113	CAFFEINE	4	200,591
CHEMBL1200468	MALATHION	4	36,800
CHEMBL1200699	DOXYCYCLINE	4	93,821
CHEMBL1201288	DANTROLENE	4	10,182
CHEMBL1201303	PYRVINIUM	4	1,797
CHEMBL1201304	INDOCYANINE GREEN ACID FORM	4	7,044
CHEMBL1219	RABEPRAZOLE	4	12,441
CHEMBL1242	PHENAZOPYRIDINE	4	4,686
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289	HALOPROGIN	4	8,799
CHEMBL1324	TOLCAPONE	4	13,819
CHEMBL1355736	THEOPHYLLINE	4	752
CHEMBL1401	NITAZOXANIDE	4	9,504
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL1544	LIOTHYRONINE	4	23,700
CHEMBL1580	PENTOSTATIN	4	103,826
CHEMBL1617	RIFAXIMIN	4	13,380
CHEMBL1643	RIBAVIRIN	4	78,049
CHEMBL1726	NISOLDIPINE	4
CHEMBL1750	CLOFARABINE	4
CHEMBL192	SILDENAFIL	4
CHEMBL193	NIFEDIPINE	4
CHEMBL19449	IBUDILAST	4
CHEMBL2103737	HYDROXOCOBALAMIN	4
CHEMBL21333	PRANLUKAST	4
CHEMBL232201	BENZIODARONE	4
CHEMBL308954	ETRAVIRINE	4
CHEMBL317052	REGADENOSON ANHYDROUS	4

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs16851030	Toxicity	3	aspirin	Asthma
rs2228079	Toxicity	3	aspirin	Asthma

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2228079	ADORA1	3	2.25	1	aspirin
rs16851030	ADORA1, MYBPH	3	3.25	1	aspirin
rs10920573	ADORA1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Adenosine receptors

Most potent curated ligand interactions (101 total), top 25:

Ligand	Action	Affinity	Parameter
capadenoson	Partial agonist	10.0	pEC50
neladenoson	Partial agonist	10.0	pEC50
PSB36	Antagonist	9.9	pKi
cyclopentyladenosine	Full agonist	9.4	pKi
5-Cl-5-deoxy-(±)-ENBA	Full agonist	9.29	pKi
[3H]CCPA	Full agonist	9.2	pKd
[3H]DPCPX	Antagonist	9.2	pKd
ABEA-X-BY630	Agonist	9.2	pKi
DPCPX	Antagonist	9.2	pKi
rolofylline	Antagonist	9.14	pKi
N(6)-cyclohexyladenosine	Agonist	9.07	pKi
LUF5981	Antagonist	9.05	pKi
derenofylline	Antagonist	9.0	pKi
FR194921	Antagonist	8.9	pKi
CPFPX	Antagonist	8.9	pKi
WRC-0571	Antagonist	8.8	pKi
(R)-PIA	Full agonist	8.7	pKi
(R,S)-PHPNECA	Full agonist	8.6	pKi
TCPA	Agonist	8.55	pKi
GR79236	Agonist	8.51	pKi
2’-Me-CCPA	Agonist	8.48	pKB
CGS 15943	Antagonist	8.46	pKi
NECA	Full agonist	8.2	pKi
tecadenoson	Agonist	8.19	pKi
compound 10 [PMID: 31306001]	Inverse agonist	8.14	pKi

Binding affinities (BindingDB)

422 measured of 505 human assays (513 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[4-[2-amino-3,5-dicyano-6-[[2-(methylcarbamoyl)-4-pyridinyl]methylsulfanyl]-4-pyridinyl]phenyl] N,N-dimethylsulfamate	EC50	0.04 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-4-[4-(2-aminoethoxy)phenyl]-3,5-dicyano-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.04 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.06 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[(6-amino-3,5-dicyano-4-phenyl-2-pyridinyl)sulfanylmethyl]-N-cyclopropylpyridine-2-carboxamide	EC50	0.08 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.1 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-4-[6-(2-hydroxyethoxy)-3-pyridinyl]-6-(2-hydroxyethylamino)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.1 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(4-methoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(4-ethoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(3,5-difluorophenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-6-(3-hydroxyazetidin-1-yl)-4-phenyl-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-6-[2-hydroxyethyl(methyl)amino]-4-phenyl-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-4-(2,3-dihydro-1,4-benzodioxin-6-yl)-6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-6-[[(2S)-2,3-dihydroxypropyl]amino]-4-phenyl-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[[3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-6-[(3R)-3-hydroxypyrrolidin-1-yl]-2-pyridinyl]sulfanylmethyl]-N-methylbenzamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[(6-amino-3,5-dicyano-4-phenyl-2-pyridinyl)sulfanylmethyl]-N-(2-aminoethyl)benzamide	EC50	0.2 nM	US-9187428: Substituted dicyanopyridines and use thereof
N-[4-(3-Cyanophenyl)-5-(4-methoxyquinazolin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide	KI	0.2 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
N-[4-(3-Cyanophenyl)-5-pyrazolo[1,5-a]pyridin-5-yl-thiazol-2-yl]morpholine-4-carboxamide	KI	0.2 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
4-[[6-amino-3,5-dicyano-4-(4-fluorophenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(3,4-difluorophenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(4-fluoro-3-methoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[(6-amino-3,5-dicyano-4-phenyl-2-pyridinyl)sulfanylmethyl]benzamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(3-propoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[1-[[6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-2-pyridinyl]sulfanyl]ethyl]-N-methylbenzamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[[3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-6-pyrrolidin-1-yl-2-pyridinyl]sulfanylmethyl]-N-ethylbenzamide	EC50	0.3 nM	US-9187428: Substituted dicyanopyridines and use thereof
N-[4-(3-Cyanophenyl)-5-(3-methylbenzimidazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide	KI	0.3 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
N-[4-(3-Cyanophenyl)-5-imidazo[1,2-a]pyridin-6-yl-thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide	KI	0.3 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
4-[[6-amino-3,5-dicyano-4-[4-(methylamino)phenyl]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[(3,5-dicyano-4-phenyl-2-pyridinyl)sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-(2,4-dimethoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-4-[4-[2-[[(2S)-2-aminopropanoyl]amino]ethoxy]phenyl]-3,5-dicyano-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[1-[[6-amino-3,5-dicyano-4-[4-(2-hydroxyethoxy)phenyl]-2-pyridinyl]sulfanyl]ethyl]benzamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[(6-amino-3,5-dicyano-4-phenyl-2-pyridinyl)oxymethyl]-N-cyclopropylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-6-(2-hydroxyethylamino)-4-(4-methoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
3-[[6-amino-3,5-dicyano-4-(4-fluorophenyl)-2-pyridinyl]sulfanylmethyl]-N-[(2R)-2,3-dihydroxypropyl]benzamide	EC50	0.4 nM	US-9187428: Substituted dicyanopyridines and use thereof
N-[4-(3-Cyanophenyl)-5-(4-methyl-6-quinolyl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide	KI	0.4 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
N-[4-(3-Cyanophenyl)-5-(3-methylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide	KI	0.4 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
4-[[6-amino-3,5-dicyano-4-[3-(2-hydroxyethoxy)phenyl]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.5 nM	US-9187428: Substituted dicyanopyridines and use thereof
N-[3-[[6-amino-3,5-dicyano-4-(3,4-difluorophenyl)-2-pyridinyl]sulfanylmethyl]phenyl]methanesulfonamide	EC50	0.5 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[6-amino-3,5-dicyano-4-[4-fluoro-3-(trifluoromethyl)phenyl]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.5 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-6-(3-hydroxyazetidin-1-yl)-4-(4-methoxyphenyl)-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.5 nM	US-9187428: Substituted dicyanopyridines and use thereof
N-cyclopropyl-4-[(3,5-dicyano-4-phenyl-6-pyrrolidin-1-yl-2-pyridinyl)sulfanylmethyl]pyridine-2-carboxamide	EC50	0.5 nM	US-9187428: Substituted dicyanopyridines and use thereof
2-[4-(ethylsulfanyl)-1H-1,3-benzodiazol-2-yl]quinoxaline	KI	0.5 nM
N-[4-(3-Cyanophenyl)-5-(7-methyl-1H-indazol-5-yl)thiazol-2-yl]-2-oxa-6-azaspiro[3.3]heptane-6-carboxamide	KI	0.5 nM	US-20250243194: ANTAGONIST OF ADENOSINE RECEPTORS
4-[5-(8-Bicyclo[2.2.1]hept-2-yl-2,6-dioxo-1-propyl-1,2,6,7-tetrahydro-purin-3-yl)-pentanoyl]-benzenesulfonyl fluoride	KD	0.53 nM
4-[[3,5-dicyano-4-phenyl-6-[(3,3,3-trifluoro-2-hydroxypropyl)amino]-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.6 nM	US-9187428: Substituted dicyanopyridines and use thereof
N-[3-[[6-amino-3,5-dicyano-4-(4-fluorophenyl)-2-pyridinyl]sulfanylmethyl]phenyl]methanesulfonamide	EC50	0.7 nM	US-9187428: Substituted dicyanopyridines and use thereof
4-[[3,5-dicyano-6-(2-hydroxyethylamino)-4-pyridin-2-yl-2-pyridinyl]sulfanylmethyl]-N-methylpyridine-2-carboxamide	EC50	0.7 nM	US-9187428: Substituted dicyanopyridines and use thereof
CHEMBL3093327	KI	0.7 nM
CHEMBL1316674	KI	0.7 nM

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
10.53	IC50	0.02951	nM	CHEMBL3770679
10.52	Ki	0.03	nM	CHEMBL1090577
10.40	EC50	0.04	nM	CHEMBL3962333
10.40	EC50	0.04	nM	CHEMBL3917744
10.29	Ki	0.051	nM	CHEMBL5177144
10.22	EC50	0.06	nM	CHEMBL3961898
10.12	Ki	0.076	nM	CHEMBL5171044
10.10	EC50	0.08	nM	CHEMBL3966416
10.02	Ki	0.096	nM	CHEMBL1093271
10.00	Ki	0.1	nM	CHEMBL2419137
10.00	EC50	0.1	nM	CAPADENOSON
10.00	EC50	0.1	nM	CHEMBL3935252
10.00	EC50	0.1	nM	CHEMBL3978419
10.00	Ki	0.1	nM	CHEMBL369573
10.00	EC50	0.1	nM	CHEMBL5174052
10.00	IC50	0.1	nM	CHEMBL5957422
9.92	EC50	0.12	nM	NECA
9.92	IC50	0.12	nM	CHEMBL411245
9.91	EC50	0.123	nM	CHEMBL5195714
9.88	EC50	0.1318	nM	CHEMBL5187330
9.85	IC50	0.14	nM	CHEMBL4533718
9.85	EC50	0.1413	nM	CHEMBL5172389
9.84	Ki	0.145	nM	CHEMBL2024114
9.82	Ki	0.15	nM	CHEMBL3317576
9.80	Ki	0.1585	nM	CHEMBL97760
9.79	Ki	0.1622	nM	CHEMBL2024114
9.77	Kd	0.17	nM	XANTHINE AMINE CONGENER
9.72	Ki	0.19	nM	CHEMBL1090578
9.72	EC50	0.19	nM	N6-CYCLOPENTYLADENOSINE
9.70	EC50	0.2	nM	CHEMBL3935524
9.70	EC50	0.2	nM	CHEMBL3921473
9.70	EC50	0.2	nM	CHEMBL3927775
9.70	EC50	0.2	nM	CHEMBL3922438
9.70	EC50	0.2	nM	CHEMBL3951148
9.70	EC50	0.2	nM	CHEMBL4113343
9.70	EC50	0.2	nM	CHEMBL3965792
9.70	EC50	0.2	nM	CHEMBL4106705
9.70	EC50	0.2	nM	CHEMBL3975241
9.70	Ki	0.2	nM	CHEMBL4092832
9.70	IC50	0.2	nM	CHEMBL5756623
9.68	IC50	0.2089	nM	NECA
9.66	Ki	0.22	nM	CHEMBL3317579
9.64	Ki	0.23	nM	CHEMBL3917647
9.62	Kd	0.24	nM	CHEMBL321218
9.62	EC50	0.2399	nM	CHEMBL5203632
9.60	Ki	0.25	nM	CHEMBL2419150
9.59	Kd	0.26	nM	CHEMBL321218
9.57	Kd	0.27	nM	CHEMBL144360
9.55	Ki	0.28	nM	CHEMBL4063997
9.55	Kd	0.28	nM	CHEMBL144360

PubChem BioAssay actives

2413 with measured affinity, of 6100 total; 50 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3S,4R,5R)-N-ethyl-3,4-dihydroxy-5-[6-[[(1R,2R)-2-phenylmethoxycyclopentyl]amino]purin-9-yl]oxolane-2-carboxamide	1281004: Agonist activity at human Adenosine A1 receptor transfected in CHO-K1 cells assessed as inhibition of forskolin-stimulated cAMP production after 30 mins by multimode microplate reader analysis	ic50	<0.0001	uM
2-amino-4-phenylindeno[1,2-d]pyrimidin-5-one	1822211: Displacement of [3H]DPCPX from A1 adenosine receptor (unknown origin) expressed in CHO cell membrane incubated for 60 mins at room temperature by NXT microplate scintillation counter analysis	ki	0.0001	uM
5-[3-(3-methoxyphenyl)propyl]-2-phenylpyrazolo[4,3-d]pyrimidin-7-amine	1185684: Displacement of [3H]-DPCPX from human adenosine A1 receptor expressed in CHO cells by scintillation counting analysis	ki	0.0001	uM
7-amino-5-oxo-2-phenyl-8H-[1,2,4]triazolo[1,5-a]pyridine-6-carbonitrile	1871359: Binding affinity to human adenosine A1A receptor measured by radioligand-based affinity assay	ki	0.0001	uM
(2R,3R,4S,5R)-2-[6-[di(cyclobutyl)methylamino]purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol	1571920: Agonist activity at human A1A adenosine receptor expressed in HEK cells assessed as inhibition of forskolin-stimulated cAMP production after 60 mins	ic50	0.0001	uM
4-[3-(8-cyclopentyl-2,6-dioxo-1-propyl-7H-purin-3-yl)propylcarbamoyl]benzenesulfonyl fluoride	32595: Dissociation constant of [3H]DPCPX binding to adenosine A1 receptor(AR) at 0.1 nM	kd	0.0002	uM
3-[3-(7-amino-2-phenylpyrazolo[4,3-d]pyrimidin-5-yl)propyl]phenol	1185684: Displacement of [3H]-DPCPX from human adenosine A1 receptor expressed in CHO cells by scintillation counting analysis	ki	0.0002	uM
3-[2-[[7-amino-2-(furan-2-yl)-[1,3]thiazolo[5,4-d]pyrimidin-5-yl]amino]ethyl]phenol	1338756: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cell membranes measured after 90 mins by scintillation counting method	ki	0.0002	uM
4-(3-amino-5-phenyl-1,2,4-triazin-6-yl)-2-chlorophenol	659090: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells after 1 hr by liquid scintillation counting	ki	0.0002	uM
8-cyclopentyl-2-(3-hydroxyphenyl)-1-propyl-7H-purin-6-one	1427557: Antagonist activity at human adenosine A1 receptor expressed in HEK293 cells assessed as reduction in CPA-mediated inhibition of forskolin-stimulated cAMP level preincubated for 15 mins followed by CPA treatment for 15 mins and subsequent addition of forskolin measured after 30 mins by HTRF assay	ki	0.0002	uM
4-[5-(8-cyclohexyl-2,6-dioxo-1-propyl-7H-purin-3-yl)pentanoyl]benzenesulfonyl fluoride	32598: Equilibrium dissociation constant for [3H]DPCPX binding to Adenosine A1 receptor from DDT1 MF2 cell membranes	kd	0.0003	uM
4-[(8-cyclohexyl-2,6-dioxo-1-propyl-7H-purin-3-yl)methyl]benzenesulfonyl fluoride	32476: Dissociation constant of [3H]DPCPX binding to adenosine A1 receptor (AR) at 200 nM	kd	0.0003	uM
4-[3-(8-cyclohexyl-2,6-dioxo-1-propyl-7H-purin-3-yl)propylcarbamoyl]benzenesulfonyl fluoride	32473: Dissociation constant of [3H]DPCPX binding to adenosine A1 receptor (AR) at 0.05 nM	kd	0.0003	uM
8-cyclopentyl-2,6-diphenyl-7H-purine	264496: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells	ki	0.0003	uM
(2R,3R,4S,5R)-2-[2-chloro-6-(cyclopropylamino)purin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1200765: Displacement of [3H]-CCPA from human recombinant adenosine A1 receptor transfected in CHO cells	ki	0.0003	uM
3-(8-cyclopentyl-2,6-dioxo-1-propyl-7H-purin-3-yl)propyl 4-fluorosulfonylbenzoate	32477: Dissociation constant of [3H]DPCPX binding to adenosine A1 receptor (AR) at 5 nM	kd	0.0003	uM
4-(cyclopentylamino)-2-phenyl-[1,2,4]triazolo[4,3-a]quinoxalin-1-one	282760: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells	ki	0.0004	uM
2-amino-4-(furan-2-yl)indeno[1,2-d]pyrimidin-5-one	1138030: Antagonist activity at human recombinant adenosine A1 receptor by cAMP assay	ki	0.0004	uM
4-[3-(8-cyclohexyl-2,6-dioxo-1-propyl-7H-purin-3-yl)propyl]benzenesulfonyl fluoride	32476: Dissociation constant of [3H]DPCPX binding to adenosine A1 receptor (AR) at 200 nM	kd	0.0004	uM
(2R,3R,4S,5R)-2-[6-(4-chloro-2-fluoroanilino)purin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1200765: Displacement of [3H]-CCPA from human recombinant adenosine A1 receptor transfected in CHO cells	ki	0.0004	uM
(2S,3S,4R,5R)-5-[6-(2-adamantylamino)purin-9-yl]-N-ethyl-3,4-dihydroxyoxolane-2-carboxamide	1281004: Agonist activity at human Adenosine A1 receptor transfected in CHO-K1 cells assessed as inhibition of forskolin-stimulated cAMP production after 30 mins by multimode microplate reader analysis	ic50	0.0004	uM
(2R,3R,4S,5R)-2-[6-(cyclopropylmethylamino)purin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1483032: Displacement of [3H]CCPA from recombinant human adenosine A1 receptor expressed in CHO cell membranes after 3 hrs by microbeta scintillation counting	ki	0.0004	uM
(2R,3R,4S,5R)-2-[6-(2-bicyclo[2.2.1]heptanylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol	414962: Displacement of [3H]CCPA from human recombinant adenosine A1 receptor expressed in CHO cells	ki	0.0005	uM
[2-amino-4-(2,2-dimethylpropyl)-5-(2-phenylethynyl)thiophen-3-yl]-(4-chlorophenyl)methanone	1162476: Allosteric enhancer activity at human adenosine A1 receptor expressed in CHO cell membranes assessed as [3H]NECA affinity constant at 1 uM (Kd = 0.87 +/- 0.04 nM)	kd	0.0005	uM
4-[5-(8-cyclopentyl-2,6-dioxo-1-propyl-7H-purin-3-yl)pentanoyl]benzenesulfonyl fluoride	32598: Equilibrium dissociation constant for [3H]DPCPX binding to Adenosine A1 receptor from DDT1 MF2 cell membranes	kd	0.0005	uM
2-(4-ethylsulfanyl-1H-benzimidazol-2-yl)quinoxaline	1798061: Human A1 Adenosine Receptor Binding Assay from Article 10.1021/jm701159t: “Derivatives of 4-Amino-6-hydroxy-2-mercaptopyrimidine as Novel, Potent, and Selective A3 Adenosine Receptor Antagonists.”	ki	0.0005	uM
2-[3-(7-amino-2-phenylpyrazolo[4,3-d]pyrimidin-5-yl)propyl]phenol	1185684: Displacement of [3H]-DPCPX from human adenosine A1 receptor expressed in CHO cells by scintillation counting analysis	ki	0.0005	uM
(2R,3R,4S,5R)-2-[6-[[(1R,2S,4R)-2-bicyclo[2.2.1]heptanyl]amino]purin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1200765: Displacement of [3H]-CCPA from human recombinant adenosine A1 receptor transfected in CHO cells	ki	0.0005	uM
(2R,3R,4S,5R)-2-[2-chloro-6-(cyclopentylamino)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol	1281004: Agonist activity at human Adenosine A1 receptor transfected in CHO-K1 cells assessed as inhibition of forskolin-stimulated cAMP production after 30 mins by multimode microplate reader analysis	ic50	0.0005	uM
8-cyclopentyl-1,3-dipropyl-7H-purine-2,6-dione	1285608: Displacement of [3H]DPCPX from human recombinant adenosine A1 receptor expressed in CHO cells	ic50	0.0005	uM
4-(2-amino-4-phenylpyrimidin-5-yl)-2-chlorophenol	1338032: Displacement of [3H]DPCPX from recombinant human adenosine A1 receptor expressed in CHO cell membranes after 1 hr by beta scintillation counting method	ki	0.0005	uM
(2R,3R,4S,5R)-2-[2-chloro-6-(cyclopropylmethylamino)purin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1483032: Displacement of [3H]CCPA from recombinant human adenosine A1 receptor expressed in CHO cell membranes after 3 hrs by microbeta scintillation counting	ki	0.0005	uM
(2R,3R,4S,5S)-2-[6-[[(1R,4S)-2-bicyclo[2.2.1]heptanyl]amino]purin-9-yl]-5-(chloromethyl)oxolane-3,4-diol	1571891: Displacement of [3H]N6-R-phenylisopropyladenosine from human A1A adenosine receptor expressed in CHO cell membranes after 60 mins by scintillation proximity assay	ki	0.0005	uM
7-(dimethylamino)-2-phenyl-1H-1,8-naphthyridin-4-one	282760: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells	ki	0.0006	uM
1-[6-(cyclopentylamino)-9-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]purin-2-yl]pyrazole-4-carboxamide	292692: Displacement of [3H]CPX from adenosine A1 receptor in DDT membranes	ki	0.0006	uM
2-chloro-4-[2-[(4-hydroxycyclohexyl)amino]-4-phenylpyrimidin-5-yl]phenol	1338032: Displacement of [3H]DPCPX from recombinant human adenosine A1 receptor expressed in CHO cell membranes after 1 hr by beta scintillation counting method	ki	0.0006	uM
(2S,3S,4R,5R)-2-(chloromethyl)-5-[6-(cyclopentylamino)purin-9-yl]oxolane-3,4-diol	414962: Displacement of [3H]CCPA from human recombinant adenosine A1 receptor expressed in CHO cells	ki	0.0006	uM
5,7-diphenyl-2-propan-2-yl-1H-imidazo[4,5-b]pyridine	277881: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells	ki	0.0006	uM
2-cyclopentyl-5,7-diphenyl-1H-imidazo[4,5-b]pyridine	277881: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells	ki	0.0006	uM
3-[(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)methylcarbamoyl]benzenesulfonyl fluoride	32471: Specific binding of [3H]CPX to the A1-adenosine receptor	kd	0.0007	uM
4-[2-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)ethylcarbamoyl]benzenesulfonyl fluoride	32471: Specific binding of [3H]CPX to the A1-adenosine receptor	kd	0.0007	uM
8-[(2,5-dioxopyrrol-1-yl)methyl]-1,3-dipropyl-7H-purine-2,6-dione	32472: Binding of [3H]-CPX to A1 adenosine receptor of DDT1 MF-2 (DDT) cells	kd	0.0007	uM
[3-(2,6-dioxo-1,3-dipropyl-7H-purin-8-yl)cyclopentyl] 2-bromoacetate	32471: Specific binding of [3H]CPX to the A1-adenosine receptor	kd	0.0007	uM
8-cyclohexyl-2,6-diphenyl-7H-purine	264496: Displacement of [3H]DPCPX from human adenosine A1 receptor expressed in CHO cells	ki	0.0007	uM
1-butyl-3-(3-hydroxypropyl)-8-(3-tricyclo[3.3.1.03,7]nonanyl)-7H-purine-2,6-dione	1687716: Displacement of [3H]CCPA from human adenosine receptor A1 expressed in CHO cell membranes incubated for 90 mins by radioligand competition assay	ki	0.0007	uM
(2R,3R,4S,5R)-2-[6-(cyclopropylamino)purin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1200765: Displacement of [3H]-CCPA from human recombinant adenosine A1 receptor transfected in CHO cells	ki	0.0007	uM
(2R,3R,4S,5R)-2-[6-[[(1R,2S,4R)-2-bicyclo[2.2.1]heptanyl]amino]-2-chloropurin-9-yl]-5-(2-ethyltetrazol-5-yl)oxolane-3,4-diol	1200765: Displacement of [3H]-CCPA from human recombinant adenosine A1 receptor transfected in CHO cells	ki	0.0007	uM
(2R,3R,4S,5R)-2-[6-amino-2-(3-hydroxy-3-phenylprop-1-ynyl)purin-9-yl]-5-(hydroxymethyl)oxolane-3,4-diol	30440: Binding affinity against Human recombinant Adenosine A1 receptor stably transfected in CHO cells using [3H]CCPA as radioligand	ki	0.0007	uM
1,3-dibutyl-8-(3-tricyclo[3.3.1.03,7]nonanyl)-7H-purine-2,6-dione	1412903: Binding affinity to human adenosine A1 receptor by radioligand displacement assay	ki	0.0007	uM
(2S,3S,4R,5R)-5-[6-[3-[6-[[2-[4-[(E)-2-(2,2-difluoro-12-thiophen-2-yl-3-aza-1-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-1(12),4,6,8,10-pentaen-4-yl)ethenyl]phenoxy]acetyl]amino]hexanoylamino]propylamino]purin-9-yl]-N-ethyl-3,4-dihydroxyoxolane-2-carboxamide	277350: Agonist activity at adenosine A1 receptor assessed as inhibition of forskolin-stimulated [3H]cAMP accumulation in CHO cells	ec50	0.0007	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases reaction, decreases reaction, affects cotreatment, increases expression, affects binding	5
Valproic Acid	decreases methylation, affects cotreatment, decreases expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
1,3-dipropyl-8-cyclopentylxanthine	affects binding	2
(+)-JQ1 compound	decreases expression	2
Fulvestrant	increases methylation, decreases reaction, increases expression, decreases expression, affects cotreatment	2
Adenosine	affects activity, affects binding, decreases activity, affects reaction	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol F	affects cotreatment, increases methylation	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
trichostatin A	decreases expression	1
arsenite	increases expression, decreases reaction	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
4-hydroxy-2-nonenal	decreases expression	1
diallyl disulfide	decreases expression, decreases reaction	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
picene	decreases expression	1
PD 81723	affects activity, affects binding, affects reaction	1
CGP 52608	affects binding, increases reaction	1
VUF 5455	affects activity, affects binding, affects reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
bisphenol B	increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

1706 unique, capped per target: 1409 binding, 292 functional, 5 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1014572	Binding	Selectivity ratio of Ki for human adenosine A1 receptor to Ki for human adenosine A3 receptor	Structure-activity relationship studies of a new series of imidazo[2,1-f]purinones as potent and selective A(3) adenosine receptor antagonists. — Bioorg Med Chem
CHEMBL3413626	Functional	Selectivity ratio of EC50 for human recombinant A3 adenosine receptor expressed in CHO cells to EC50 for human recombinant A1 adenosine receptor expressed in CHO cells by cAMP assay	In vivo phenotypic screening for treating chronic neuropathic pain: modification of C2-arylethynyl group of conformationally constrained A3 adenosine receptor agonists. — J Med Chem
CHEMBL3863976	ADMET	Antagonist activity at adenosine A1 receptor (unknown origin)	Biphenyl Pyridazinone Derivatives as Inhaled PDE4 Inhibitors: Structural Biology and Structure-Activity Relationships. — J Med Chem

Cellosaurus cell lines

9 cell lines: 4 spontaneously immortalized cell line, 3 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0S0	ACTOne ADORA1	Transformed cell line	Female
CVCL_D8H6	Ubigene HCT 116 ADORA1 KO	Cancer cell line	Male
CVCL_E7S6	MultiScreen HEK293T A1 receptor	Transformed cell line	Female
CVCL_H362	293/ADORA1/Galpha15	Transformed cell line	Female
CVCL_H383	CHO-K1/ADORA1/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KU73	cAMP Hunter CHO-K1 ADORA1 Gi	Spontaneously immortalized cell line	Female
CVCL_KW23	PathHunter CHO-K1 ADORA1 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_RU27	CHO-K1 AequoScreen ADORA1	Spontaneously immortalized cell line	Female
CVCL_ZK53	Tango ADORA1-bla U2OS	Cancer cell line	Female

Clinical trials (associated diseases)

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