ADCY2

Summary

ADCY2 (adenylate cyclase 2, HGNC:233) is a protein-coding gene on chromosome 5p15.31, encoding Adenylate cyclase type 2 (Q08462). Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.

This gene encodes a member of the family of adenylate cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP). This enzyme is insensitive to Ca(2+)/calmodulin, and is stimulated by the G protein beta and gamma subunit complex.

Source: NCBI Gene 108 — RefSeq curated summary.

At a glance

• GWAS associations: 24
• Clinical variants (ClinVar): 120 total — 2 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_020546

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:233
Approved symbol	ADCY2
Name	adenylate cyclase 2
Location	5p15.31
Locus type	gene with protein product
Status	Approved
Aliases	HBAC2, KIAA1060, AC2
Ensembl gene	ENSG00000078295
Ensembl biotype	protein_coding
OMIM	103071
Entrez	108

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000338316, ENST00000382531, ENST00000484965, ENST00000489501, ENST00000493243, ENST00000498598, ENST00000513693, ENST00000515681, ENST00000915365, ENST00000915366, ENST00000915367, ENST00000915368, ENST00000915369, ENST00000915370, ENST00000915371, ENST00000915372, ENST00000915373, ENST00000915374, ENST00000915375

RefSeq mRNA: 1 — MANE Select: NM_020546 NM_020546

CCDS: CCDS3872

Canonical transcript exons

ENST00000338316 — 25 exons

Exon	Start	End
ENSE00001376945	7826719	7830081
ENSE00001530243	7396138	7396506
ENSE00001615623	7724545	7724614
ENSE00001621363	7712856	7712899
ENSE00001633922	7690691	7690839
ENSE00001639913	7414573	7414770
ENSE00001645222	7706744	7706902
ENSE00001656584	7717157	7717237
ENSE00001658446	7727164	7727261
ENSE00001664852	7757449	7757586
ENSE00001680202	7698247	7698374
ENSE00001714470	7709211	7709387
ENSE00001722174	7772932	7773101
ENSE00001729941	7707706	7707838
ENSE00001736748	7743668	7743752
ENSE00001772743	7766687	7766806
ENSE00001783162	7695752	7695863
ENSE00003502714	7626167	7626316
ENSE00003513934	7520738	7520899
ENSE00003551409	7789642	7789800
ENSE00003559114	7820565	7820689
ENSE00003578626	7804585	7804692
ENSE00003593309	7816866	7816980
ENSE00003665473	7784365	7784449
ENSE00003690128	7802218	7802364

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 97.75.

FANTOM5 (CAGE): breadth broad, TPM avg 4.8422 / max 182.5474, expressed in 363 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55655	3.0077	343
55659	0.4461	62
55656	0.3210	126
55654	0.2326	139
55657	0.1683	64
55658	0.1315	69
55660	0.1296	46
55662	0.1180	53
55669	0.0846	47
55661	0.0845	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	97.75	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.67	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	97.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.28	gold quality
entorhinal cortex	UBERON:0002728	97.24	gold quality
postcentral gyrus	UBERON:0002581	97.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.81	gold quality
biceps brachii	UBERON:0001507	96.79	gold quality
deltoid	UBERON:0001476	96.71	gold quality
endothelial cell	CL:0000115	96.65	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.65	gold quality
superior frontal gyrus	UBERON:0002661	96.63	gold quality
skeletal muscle tissue	UBERON:0001134	96.46	gold quality
diaphragm	UBERON:0001103	96.37	gold quality
parietal lobe	UBERON:0001872	96.37	gold quality
gluteal muscle	UBERON:0002000	96.36	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.29	gold quality
tibialis anterior	UBERON:0001385	96.17	gold quality
triceps brachii	UBERON:0001509	96.09	gold quality
CA1 field of hippocampus	UBERON:0003881	95.92	gold quality
inferior olivary complex	UBERON:0002127	95.62	gold quality
cranial nerve II	UBERON:0000941	94.98	gold quality
muscle of leg	UBERON:0001383	94.84	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.81	gold quality
primary visual cortex	UBERON:0002436	94.80	gold quality
temporal lobe	UBERON:0001871	94.72	gold quality
gastrocnemius	UBERON:0001388	94.68	gold quality
muscle organ	UBERON:0001630	94.68	gold quality
orbitofrontal cortex	UBERON:0004167	94.37	gold quality
occipital lobe	UBERON:0002021	93.98	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2259.73
E-HCAD-35	yes	89.06
E-ANND-3	yes	6.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

142 targeting ADCY2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-548AZ-3P	99.82	70.56	3549

Literature-anchored findings (GeneRIF, showing 11)

• AC2 interacts with RXFP1 through AKAP79, whereas the association with PDE4D3 and PKA depends upon beta-arrestin 2 binding to Ser704. (PMID:20664520)
• AC2 and AC4 isoforms, stimulated by GTP binding protein betagamma subunits, are expressed in bronchial nonlipid raft membrane fractions where they colocalize with and couple to prostanoid EP2 receptors. (PMID:21228062)
• Data suggest that SPARCL1, Shp2, MSH2, E-cadherin, p53, ADCY-2 and MAPK are potential prognostic markers in colorectal cancer. (PMID:21528083)
• A replication of association between two SNPs previously associated with COPD (CHRNA3/5 and IREB2), as well as an association with COPD of one locus initially associated with lung function (ADCY2). (PMID:22461431)
• AGS3 reduced D(2L)DR-mediated sensitization of AC1 and AC2. (PMID:23504261)
• AKAP79, PKC, PKA and PDE4 participate in a Gq-linked muscarinic receptor and adenylate cyclase 2 cAMP signalling complex. (PMID:23889134)
• Our present study defines an AC2 cAMP signaling compartment that specifically regulates IL-6 expression in bronchial smooth muscle cells. (PMID:24363043)
• In patients receiving capecitabine monotherapy, rs4702484, located in ADCY2 and close to MTRR, was associated with slightly reduced PFS for homozygous wild-type patients (CC 6.2 vs. CT 8.0 months; P=0.018). (PMID:25815774)
• Association of adenylate cyclase-2 gene polymorphism with bipolar disorder. (PMID:32447269)
• Investigation of the impact of an ADCY2 polymorphism as a predictive biomarker in bipolar disorder, suicide tendency and response to lithium carbonate therapy: the first report from Iran. (PMID:32893730)
• circSLC25A13 acts as a ceRNA to regulate AML progression via miR-616-3p/ADCY2 axis. (PMID:37493101)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	adcy2b	ENSDARG00000014588
danio_rerio	adcy2a	ENSDARG00000058392
mus_musculus	Adcy2	ENSMUSG00000021536
rattus_norvegicus	Adcy2	ENSRNOG00000032150

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), ADCY8 (ENSG00000155897), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Adenylate cyclase type 2 — Q08462 (reviewed: Q08462)

Alternative names: ATP pyrophosphate-lyase 2, Adenylate cyclase type II, Adenylyl cyclase 2

All UniProt accessions (3): Q08462, D6REB8, H0YA58

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling. Down-stream signaling cascades mediate changes in gene expression patterns and lead to increased IL6 production. Functions in signaling cascades downstream of the muscarinic acetylcholine receptors.

Subunit / interactions. Interacts with RAF1. Interacts with GNAS. Interacts with the G protein beta and gamma subunit complex.

Subcellular location. Membrane. Cell membrane. Cytoplasm.

Tissue specificity. Detected in zona glomerulosa and zona fasciculata in the adrenal gland (at protein level). Expressed in brain, especially in caudate nucleus, cerebellum and hippocampus.

Post-translational modifications. Phosphorylated by RAF1.

Activity regulation. Activated by forskolin. Is not activated by calmodulin. Inhibited by calcium ions, already at micromolar concentration. Activated by the G protein alpha subunit GNAS. Activated by the G protein beta and gamma subunit complex. Phosphorylation by RAF1 results in its activation. Phosphorylation by PKC activates the enzyme.

Cofactor. Binds 2 magnesium ions per subunit. Is also active with manganese (in vitro).

Domain organisation. The protein contains two modules with six transmembrane helices each; both are required for catalytic activity. Isolated N-terminal or C-terminal guanylate cyclase domains have no catalytic activity, but when they are brought together, enzyme activity is restored. The active site is at the interface of the two domains. Both contribute substrate-binding residues, but the catalytic metal ions are bound exclusively via the N-terminal guanylate cyclase domain.

Similarity. Belongs to the adenylyl cyclase class-4/guanylyl cyclase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q08462-1	1	yes
Q08462-2	2

RefSeq proteins (1): NP_065433* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001054	A/G_cyclase	Domain
IPR009398	Adcy_conserved_dom	Domain
IPR018297	A/G_cyclase_CS	Conserved_site
IPR029787	Nucleotide_cyclase	Homologous_superfamily
IPR030672	Adcy	Family
IPR032628	AC_N	Domain

Pfam: PF00211, PF06327, PF16214

Enzyme classification (BRENDA):

• EC 4.6.1.1 — adenylate cyclase (BRENDA: 120 organisms, 167 substrates, 404 inhibitors, 155 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0005–8.78	135
MGATP2-	0.009–2.2	4
MNATP2-	0.067–0.086	2
ADENYLIMIDODIPHOSPHATE	0.33	1
CAMP	14	1
DATP	0.44	1
DEOXYCAMP	13	1
DIPHOSPHATE	1.9	1
GTP	1.38	1

Catalyzed reactions (Rhea), 1 shown:

• ATP = 3’,5’-cyclic AMP + diphosphate (RHEA:15389)

UniProt features (40 total): transmembrane region 12, binding site 12, topological domain 3, region of interest 2, modified residue 2, glycosylation site 2, splice variant 2, sequence variant 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08462-F1	78.91	0.35

Functional residue map

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

Ligand- & substrate-binding residues (12): 295–300; 295; 295; 296; 337–339; 339; 339; 383; 939; 1019–1021; 1026–1030; 1066

Post-translational modifications (2): 491, 544

Glycosylation sites (2): 713, 716

Function

Pathways and Gene Ontology

Reactome pathways

46 pathways

ID	Pathway
R-HSA-163359	Glucagon signaling in metabolic regulation
R-HSA-163615	PKA activation
R-HSA-164378	PKA activation in glucagon signalling
R-HSA-170660	Adenylate cyclase activating pathway
R-HSA-170670	Adenylate cyclase inhibitory pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-418594	G alpha (i) signalling events
R-HSA-418597	G alpha (z) signalling events
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-5610787	Hedgehog ‘off’ state
R-HSA-9634597	GPER1 signaling
R-HSA-9660821	ADORA2B mediated anti-inflammatory cytokines production
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-111885	Opioid Signalling
R-HSA-111931	PKA-mediated phosphorylation of CREB
R-HSA-111933	Calmodulin induced events
R-HSA-111996	Ca-dependent events
R-HSA-111997	CaM pathway
R-HSA-112040	G-protein mediated events
R-HSA-112043	PLC beta mediated events
R-HSA-112314	Neurotransmitter receptors and postsynaptic signal transmission
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-1430728	Metabolism
R-HSA-1489509	DAG and IP3 signaling
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-1643685	Disease
R-HSA-372790	Signaling by GPCR

MSigDB gene sets: 260 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, VALK_AML_WITH_FLT3_ITD, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, GOBP_CELLULAR_RESPONSE_TO_LIPID, JAEGER_METASTASIS_DN, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, REACTOME_G_ALPHA_Z_SIGNALLING_EVENTS, GOBP_CELLULAR_RESPONSE_TO_FLUID_SHEAR_STRESS, GOBP_CAMP_BIOSYNTHETIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, MEF2_02, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS

GO Biological Process (9): renal water homeostasis (GO:0003091), cAMP biosynthetic process (GO:0006171), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), intracellular signal transduction (GO:0035556), cellular response to glucagon stimulus (GO:0071377), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), cellular response to forskolin (GO:1904322), cyclic nucleotide biosynthetic process (GO:0009190)

GO Molecular Function (9): magnesium ion binding (GO:0000287), adenylate cyclase activity (GO:0004016), ATP binding (GO:0005524), adenylate cyclase binding (GO:0008179), manganese ion binding (GO:0030145), nucleotide binding (GO:0000166), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849), metal ion binding (GO:0046872)

GO Cellular Component (5): cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), dendrite (GO:0030425), membrane raft (GO:0045121)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
GPCR downstream signalling	3
G-protein mediated events	2
Anti-inflammatory response favouring Leishmania parasite infection	2
Integration of energy metabolism	1
PKA-mediated phosphorylation of CREB	1
Glucagon signaling in metabolic regulation	1
Activation of GABAB receptors	1
Aquaporin-mediated transport	1
Signaling by Hedgehog	1
G alpha (s) signalling events	1
Response of endothelial cells to shear stress	1
G alpha (i) signalling events	1
Calmodulin induced events	1
CaM pathway	1
PLC beta mediated events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
cellular anatomical structure	2
renal system process	1
multicellular organismal-level water homeostasis	1
purine ribonucleotide biosynthetic process	1
cyclic nucleotide biosynthetic process	1
cAMP metabolic process	1
adenylate cyclase activity	1
G protein-coupled receptor signaling pathway	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
signal transduction	1
response to glucagon	1
cellular response to peptide hormone stimulus	1
cellular response to laminar fluid shear stress	1
vascular endothelial cell response to fluid shear stress	1
cellular response to lipid	1
cellular response to alcohol	1
cellular response to ketone	1
response to forskolin	1
nucleotide biosynthetic process	1
cyclic nucleotide metabolic process	1
metal ion binding	1
cyclase activity	1
phosphorus-oxygen lyase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
enzyme binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
lyase activity	1
cation binding	1
membrane	1
cell periphery	1
neuron projection	1
dendritic tree	1
membrane microdomain	1

Protein interactions and networks

STRING

1610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCY2	RGS2	P41220	674
ADCY2	TMTC1	Q8IUR5	657
ADCY2	PRKACA	P17612	591
ADCY2	CACNA1C	Q13936	545
ADCY2	POMC	P01189	508
ADCY2	SUCLG2	Q96I99	488
ADCY2	AKAP5	P24588	485
ADCY2	FASTKD3	Q14CZ7	479
ADCY2	ADCYAP1	P18509	476
ADCY2	TENT4A	Q5XG87	475
ADCY2	GRM1	Q13255	468
ADCY2	CACNA1D	Q01668	466
ADCY2	PLCB1	Q9NQ66	461
ADCY2	TP53	P04637	447
ADCY2	FYN	P06241	438

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ADCY2	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
M		psi-mi:“MI:0914”(association)	0.350
ADCY2	ANKMY2	psi-mi:“MI:0914”(association)	0.350
GNAS	ADCY2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (14): ADCY2 (Co-localization), DRD4 (FRET), GNG2 (FRET), ADCY2 (Two-hybrid), ADCY2 (Proximity Label-MS), ADCY5 (Co-fractionation), EMC7 (Affinity Capture-MS), RNF181 (Affinity Capture-MS), GDE1 (Affinity Capture-MS), ANKMY2 (Affinity Capture-MS), ADCY2 (Positive Genetic), ADCY2 (Cross-Linking-MS (XL-MS)), CLTC (Cross-Linking-MS (XL-MS)), ADCY2 (Affinity Capture-RNA)

ESM2 similar proteins: A0A078BQP2, A0A131MCZ8, A3KGB4, A5LFX5, A8MYU2, B8A4F4, D4A6Z8, F1S5L4, O18784, O35119, O54982, O60146, O60706, P0C550, P26769, P48995, P79100, P97564, Q08462, Q0IIM8, Q0JKV1, Q12791, Q17I16, Q38898, Q38998, Q5GJ77, Q61056, Q61586, Q6J5K9, Q7XUW4, Q80TL1, Q80YE7, Q84M24, Q8CF82, Q8GXE6, Q8K442, Q8K448, Q8VZM7, Q8WWZ7, Q940Y9

Diamond homologs: A0A0U1RPR8, A8WPG9, A8XQC7, H2L002, N1NVB7, O02298, O02740, O16544, O16715, O19179, O54865, O60266, O60503, O62179, O64784, O75343, O88444, P0A4Y1, P11528, P16065, P16068, P18910, P19686, P19687, P19754, P20595, P21932, P22717, P23897, P25092, P26769, P26770, P32870, P33402, P40137, P40145, P40146, P51828, P51830, P51839

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY2
ADCY2	“up-regulates quantity”	“3’,5’-cyclic AMP”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	82
Likely benign	9
Benign	6

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
151161	GRCh38/hg38 5p15.31-15.2(chr5:7670933-13623997)x1	Pathogenic
563032	GRCh37/hg19 5p15.32-15.2(chr5:5884444-14122539)x3	Pathogenic
218968	t(5;16)(p15.31;q23.1)	Likely pathogenic

SpliceAI

5674 predictions. Top by Δscore:

Variant	Effect	Δscore
5:7396502:GGCTG:G	donor_gain	1.0000
5:7396503:GCTG:G	donor_gain	1.0000
5:7396503:GCTGG:G	donor_gain	1.0000
5:7396507:G:GG	donor_gain	1.0000
5:7410188:G:GT	donor_gain	1.0000
5:7414563:A:AG	acceptor_gain	1.0000
5:7414564:T:G	acceptor_gain	1.0000
5:7414568:CTCA:C	acceptor_loss	1.0000
5:7414569:TCA:T	acceptor_loss	1.0000
5:7414571:A:AG	acceptor_gain	1.0000
5:7414571:AG:A	acceptor_gain	1.0000
5:7414571:AGG:A	acceptor_loss	1.0000
5:7414572:G:A	acceptor_loss	1.0000
5:7414572:G:GG	acceptor_gain	1.0000
5:7414572:GG:G	acceptor_gain	1.0000
5:7414572:GGAA:G	acceptor_gain	1.0000
5:7414771:G:GG	donor_gain	1.0000
5:7414771:GTA:G	donor_loss	1.0000
5:7520729:T:TA	acceptor_gain	1.0000
5:7520732:CCGTA:C	acceptor_loss	1.0000
5:7520733:CGTAG:C	acceptor_loss	1.0000
5:7520734:GTA:G	acceptor_loss	1.0000
5:7520735:TA:T	acceptor_loss	1.0000
5:7520736:A:AG	acceptor_gain	1.0000
5:7520736:A:AT	acceptor_loss	1.0000
5:7520736:AG:A	acceptor_gain	1.0000
5:7520737:G:GG	acceptor_gain	1.0000
5:7520737:GG:G	acceptor_gain	1.0000
5:7520737:GGT:G	acceptor_gain	1.0000
5:7520737:GGTA:G	acceptor_gain	1.0000

AlphaMissense

7215 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:7690698:T:C	L243P	1.000
5:7690713:T:C	L248P	1.000
5:7690716:C:A	P249Q	1.000
5:7690802:T:C	F278L	1.000
5:7690804:C:A	F278L	1.000
5:7690804:C:G	F278L	1.000
5:7690838:A:C	S290R	1.000
5:7695752:C:A	S290R	1.000
5:7695752:C:G	S290R	1.000
5:7695762:G:C	A294P	1.000
5:7695763:C:A	A294D	1.000
5:7695765:G:C	D295H	1.000
5:7695766:A:C	D295A	1.000
5:7695766:A:G	D295G	1.000
5:7695766:A:T	D295V	1.000
5:7695769:T:A	I296N	1.000
5:7695777:T:C	F299L	1.000
5:7695778:T:C	F299S	1.000
5:7695779:T:A	F299L	1.000
5:7695779:T:G	F299L	1.000
5:7695814:T:C	L311P	1.000
5:7695817:T:A	V312D	1.000
5:7695826:T:C	L315P	1.000
5:7695835:T:C	L318P	1.000
5:7695837:T:A	F319I	1.000
5:7695837:T:C	F319L	1.000
5:7695839:T:A	F319L	1.000
5:7695839:T:G	F319L	1.000
5:7695846:T:C	F322L	1.000
5:7695847:T:C	F322S	1.000

dbSNP variants (sampled 300 via entrez): RS1000001751 (5:7503802 A>G), RS1000016388 (5:7583627 G>A), RS1000017497 (5:7759939 T>C), RS1000017523 (5:7708089 A>C,G,T), RS1000019598 (5:7717840 C>T), RS1000020788 (5:7543580 T>C), RS1000022740 (5:7624399 C>A), RS1000030822 (5:7411436 T>G), RS1000044401 (5:7799158 A>G), RS1000048487 (5:7447532 TC>T), RS1000048513 (5:7760224 T>C), RS1000051283 (5:7748556 A>G), RS1000054464 (5:7411925 A>G), RS1000062388 (5:7727751 TGTTATAGGTCAAG>T), RS1000062982 (5:7711417 A>C)

Disease associations

OMIM: gene MIM:103071 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST001368_19	Capecitabine sensitivity	5.000000e-08
GCST001368_5	Capecitabine sensitivity	6.000000e-07
GCST001525_18	Visceral fat	4.000000e-06
GCST002308_5	Mean arterial pressure (alcohol consumption interaction)	7.000000e-07
GCST002385_4	Bipolar disorder	1.000000e-08
GCST003075_120	Cognitive decline rate in late mild cognitive impairment	1.000000e-07
GCST003075_91	Cognitive decline rate in late mild cognitive impairment	3.000000e-08
GCST003489_9	Food addiction	6.000000e-07
GCST003859_9	Oropharynx cancer	4.000000e-06
GCST004001_4	Bipolar disorder or attention deficit hyperactivity disorder	1.000000e-07
GCST004002_1	Bipolar disorder (age of onset <21) or attention deficit hyperactivity disorder	2.000000e-08
GCST006417_19	Plasma factor VII activating protease levels	1.000000e-08
GCST008103_20	Bipolar disorder	1.000000e-08
GCST008115_4	Bipolar I disorder	7.000000e-09
GCST008526_50	Coffee consumption	2.000000e-09
GCST008554_2	Atorvastatin-induced myopathy	3.000000e-06
GCST008559_10	Anxiety and stress-related disorders	7.000000e-07
GCST008667_3	Smoking status (heavy vs never)	4.000000e-07
GCST009183_5	Posterior-cingulate cortex volume	2.000000e-06
GCST009193_4	Pars opercularis volume	4.000000e-06
GCST011125_5	Caffeine consumption from coffee	1.000000e-09
GCST011126_9	Caffeine consumption from coffee or tea	2.000000e-12
GCST011741_32	LDL cholesterol levels in HIV infection	3.000000e-06
GCST012465_2	Bipolar disorder	2.000000e-09

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0007710	cognitive decline measurement
EFO:0007829	eating behaviour
EFO:0007830	food addiction measurement
EFO:0009963	bipolar I disorder
EFO:0006781	coffee consumption measurement
EFO:0010098	stress-related disorder
EFO:0006527	smoking status measurement
EFO:0010091	tea consumption measurement
EFO:0004611	low density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2097167 (PROTEIN FAMILY), CHEMBL3760 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1544938	Efficacy	3	antipsychotics	Schizophrenia
rs4702484	Efficacy	4	capecitabine	Colorectal Neoplasms

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1544938	ADCY2	3	1.62	1	antipsychotics
rs4702484	ADCY2	4	-1.75	1	capecitabine
rs6883259	ADCY2		0.00	0
rs2290910	ADCY2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenylyl cyclases (ACs)

ChEMBL bioactivities

60 potent at pChembl≥5 of 67 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.06	Ki	0.88	nM	CHEMBL3142312
8.77	Ki	1.7	nM	CHEMBL3142318
8.77	Ki	1.7	nM	CHEMBL3142332
8.72	Ki	1.9	nM	CHEMBL3142329
8.60	Ki	2.5	nM	CHEMBL3142331
8.59	Ki	2.6	nM	CHEMBL2369777
8.41	Ki	3.9	nM	CHEMBL2369525
8.38	Ki	4.2	nM	CHEMBL2369778
8.11	Ki	7.8	nM	CHEMBL3142313
7.85	Ki	14	nM	CHEMBL66087
7.77	Ki	17	nM	CHEMBL418135
7.70	Ki	20	nM	CHEMBL293907
7.54	Ki	29	nM	CHEMBL305151
7.48	Ki	33	nM	CHEMBL62123
7.16	Ki	69	nM	CHEMBL305151
7.15	EC50	71	nM	(R)-SKF-38393
7.05	EC50	90	nM	CHEMBL4751732
6.96	Ki	110	nM	CHEMBL62412
6.84	Ki	144	nM	CHEMBL64475
6.77	EC50	170	nM	CHEMBL4750740
6.68	EC50	210	nM	CHEMBL4740707
6.63	EC50	236	nM	CHEMBL4777571
6.59	Ki	254	nM	CHEMBL62444
6.52	EC50	300	nM	CHEMBL4761309
6.52	EC50	301	nM	CHEMBL4762531
6.52	Ki	300	nM	CHEMBL62892
6.51	EC50	310	nM	CHEMBL4744648
6.50	Ki	317	nM	CHEMBL64646
6.46	EC50	345	nM	CHEMBL4758446
6.37	EC50	430	nM	CHEMBL4764988
6.28	EC50	520	nM	CHEMBL4784488
6.28	EC50	530	nM	CHEMBL4779970
6.21	Ki	610	nM	CHEMBL418468
6.17	EC50	670	nM	CHEMBL4789237
6.16	EC50	692	nM	CHEMBL4744718
6.12	EC50	750	nM	CHEMBL4745593
6.11	EC50	770	nM	CHEMBL4786932
6.02	EC50	960	nM	CHEMBL4763908
6.00	Ki	1000	nM	CHEMBL64955
5.97	EC50	1081	nM	CHEMBL4760543
5.92	EC50	1200	nM	CHEMBL4754188
5.89	EC50	1300	nM	CHEMBL4760850
5.89	EC50	1288	nM	CHEMBL4754971
5.80	EC50	1600	nM	CHEMBL4760156
5.79	EC50	1640	nM	CHEMBL4751176
5.69	EC50	2060	nM	CHEMBL4800693
5.51	EC50	3078	nM	CHEMBL4745662
5.51	EC50	3120	nM	CHEMBL4799136
5.47	EC50	3367	nM	CHEMBL4761233
5.46	EC50	3440	nM	CHEMBL4795137

PubChem BioAssay actives

60 with measured affinity, of 229 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
(4R,7S,10S,13S,16S)-N-[(2R)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0009	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0017	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-[[(2R)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0017	uM
(4R,7S,10S,13S,16S)-N-[(2R)-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0019	uM
(4R,7S,10S,13S,16S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34312: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0025	uM
(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-N-[(2S)-5-(diaminomethylideneamino)-1-[[(2S)-1,6-diamino-1-oxohexan-2-yl]amino]-1-oxopentan-2-yl]-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0026	uM
(2S)-N-[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-1-[(4R,7S,10S,13S,16R)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]pyrrolidine-2-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0039	uM
(4R,7S,10S,13S,16R)-N-[(2S)-6-amino-1-[[(2S)-1-amino-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carboxamide	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0042	uM
(2S)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S)-7-(2-amino-2-oxoethyl)-13-benzyl-20,20-dicyclopentyl-16-[(4-ethoxyphenyl)methyl]-6,9,12,15,18-pentaoxo-10-propan-2-yl-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	34311: Compound was evaluated for the inhibition constant for inhibition of 8-lysine-vasopressin stimulated adenylate cyclase of pig kidney medullary membrane	ki	0.0078	uM
3-[[4-[1-[4-(2,4-dichlorophenyl)anilino]-1-oxooctan-2-yl]oxybenzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0140	uM
3-[[4-[1-[4-(1-benzofuran-2-yl)anilino]-1-oxooctan-2-yl]oxybenzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0170	uM
3-[[4-[2-[[4-(1-benzofuran-2-yl)phenyl]carbamoyl]octyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0200	uM
3-[[4-[3-[4-(1-benzofuran-2-yl)anilino]-2-(4-tert-butylphenyl)-3-oxopropyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0290	uM
3-[[4-[2-(4-tert-butylphenyl)-3-[4-(2,4-dichlorophenyl)anilino]-3-oxopropyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.0330	uM
(5R)-5-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol	34592: Compound was tested for the adenylate cyclase stimulation	ec50	0.0710	uM
(1S,3aS,6aR)-5’-bromo-5-(2-chlorophenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.0900	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-[4-(trifluoromethoxy)anilino]propyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.1100	uM
3-[[4-[1-(4-tert-butylphenyl)-2-oxo-2-(4-phenylanilino)ethoxy]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.1440	uM
(1S,3aS,6aR)-5-(2-chlorophenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.1700	uM
(1S,3aS,6aR)-5-(3,4-dimethylphenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.2100	uM
(1S,3aS,6aR)-5’-chloro-5-(2-chlorophenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.2360	uM
3-[[4-[[(4-tert-butylcyclohexyl)-[[4-(trifluoromethoxy)phenyl]carbamoyl]amino]methyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.2540	uM
(1S,3aS,6aR)-5-(2-chlorophenyl)-5’-methyl-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.3000	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-(4-phenylanilino)propyl]benzoyl]amino]propanoic acid	34296: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.3000	uM
(1S,3aS,6aR)-4’-chloro-5-(2-chlorophenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.3010	uM
(1S,3aS,6aR)-1-(4-chlorophenyl)-5-(3,5-dimethylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.3100	uM
4-[1-(4-tert-butylphenyl)-2-oxo-2-(4-phenylanilino)ethoxy]-N-(2H-tetrazol-5-yl)benzamide	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.3170	uM
(1S,3aS,6aR)-5-(2-chlorophenyl)-4’-fluoro-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.3450	uM
(1S,3aS,6aR)-1-(4-chlorophenyl)-5-(4-ethylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.4300	uM
(1S,3aS,6aR)-5-(3-chloro-4-fluorophenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.5200	uM
(1S,3aS,6aR)-1-(4-chlorophenyl)-5-(4-fluorophenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.5300	uM
3-[[4-[2-(4-tert-butylphenyl)-3-oxo-3-(quinolin-3-ylamino)propyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	0.6100	uM
(1S,3aS,6aR)-1-(4-ethylphenyl)-5-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.6700	uM
(1S,3aS,6aR)-5-(2-chlorophenyl)-5’-fluoro-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.6920	uM
(1S,3aS,6aR)-5-(3-chloro-4-methylphenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.7500	uM
(1S,3aS,6aR)-5-(2-fluoro-4-methylphenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.7700	uM
(1S,3aS,6aR)-5-(3-methoxyphenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	0.9600	uM
3-[[4-[2-(4-tert-butylphenyl)-3-[4-(hydroxymethyl)anilino]-3-oxopropyl]benzoyl]amino]propanoic acid	34294: In vitro inhibitory activity against glucagon induced human adenylate cyclase	ki	1.0000	uM
(1S,3aS,6aR)-5-(2-chlorophenyl)-4’-methyl-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	1.0810	uM
(1S,3aS,6aR)-5-(2,5-dimethoxyphenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	1.2000	uM
(1S,3aS,6aR)-5-cyclohexyl-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	1.2880	uM
(1S,3aS,6aR)-5-(4-fluorophenyl)-1-(4-propan-2-ylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	1.3000	uM
(1S,3aS,6aR)-1-(3-methoxyphenyl)-5-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	1.6000	uM
(1S,3aS,6aR)-5-(4-fluorophenyl)-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	1.6400	uM
(1S,3aS,6aR)-5-(4-chlorophenyl)-1-phenylspiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	2.0600	uM
(1S,3aS,6aR)-5-methyl-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	3.0780	uM
(1S,3aS,6aR)-5-(5-chloro-2-methylphenyl)-1-phenylspiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	3.1200	uM
(1S,3aS,6aR)-5-cyclopropyl-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	3.3670	uM
(1S,3aS,6aR)-5-cyclopentyl-1-(4-methylphenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	3.4400	uM
(1S,3aS,6aR)-1-(4-chlorophenyl)-5-(3-fluorophenyl)spiro[3a,6a-dihydro-1H-furo[3,4-c]pyrrole-3,2’-indene]-1’,3’,4,6-tetrone	1690429: Agonist activity at recombinant human AC2 expressed in HEK293 cells assessed as increase in cAMP level measured after 30 mins by LANCE Ultra cAMP Detection kit method	ec50	3.5300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	5
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
bisphenol A	increases expression	1
terbufos	increases methylation	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
clothianidin	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Amphotericin B	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	decreases expression	1
Fonofos	increases methylation	1
Endosulfan	decreases expression	1
Lead	affects expression	1
Methapyrilene	affects methylation	1
Methyl Methanesulfonate	decreases expression	1
Parathion	increases methylation	1
Pesticides	decreases methylation	1
Selenium	affects cotreatment, increases expression, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Triclosan	decreases expression	1
Vitamin E	affects cotreatment, increases expression	1

ChEMBL screening assays

31 unique, capped per target: 29 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3284336	Binding	Agonist activity at adenylyl cyclase (unknown origin) at 1.35 x 10’-4 M	Synthesis of a fragment of human parathyroid hormore, hPTH-(44-68). — J Med Chem
CHEMBL645298	Functional	In vitro antagonist activity was measured by inhibition of vasopressin-stimulated adenylate cyclase in renal medullary preparation in pig	Dicarbavasopressin antagonist analogues exhibit reduced in vivo agonist activity. — J Med Chem

Clinical trials (associated diseases)

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