ADCY8

Summary

ADCY8 (adenylate cyclase 8, HGNC:239) is a protein-coding gene on chromosome 8q24.22, encoding Adenylate cyclase type 8 (P40145). Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion.

Adenylate cyclase is a membrane bound enzyme that catalyses the formation of cyclic AMP from ATP. The enzymatic activity is under the control of several hormones, and different polypeptides participate in the transduction of the signal from the receptor to the catalytic moiety. Stimulatory or inhibitory receptors (Rs and Ri) interact with G proteins (Gs and Gi) that exhibit GTPase activity and they modulate the activity of the catalytic subunit of the adenylyl cyclase

Source: NCBI Gene 114 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 183 total — 6 pathogenic, 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001115

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:239
Approved symbol	ADCY8
Name	adenylate cyclase 8
Location	8q24.22
Locus type	gene with protein product
Status	Approved
Aliases	HBAC1, AC8
Ensembl gene	ENSG00000155897
Ensembl biotype	protein_coding
OMIM	103070
Entrez	114

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000286355, ENST00000377928, ENST00000522949, ENST00000912159, ENST00000912160, ENST00000912161

RefSeq mRNA: 1 — MANE Select: NM_001115 NM_001115

CCDS: CCDS6363

Canonical transcript exons

ENST00000286355 — 18 exons

Exon	Start	End
ENSE00000703467	130836277	130836449
ENSE00000887775	130785383	130785475
ENSE00000887776	130800426	130800572
ENSE00000887777	130847424	130847513
ENSE00000887778	130849602	130849803
ENSE00000981443	130867846	130867946
ENSE00001089845	130814069	130814227
ENSE00001089846	130821342	130821420
ENSE00001089849	130783691	130783805
ENSE00001137856	130780301	130780877
ENSE00001263169	130884564	130884761
ENSE00001263179	130909708	130909866
ENSE00001263188	130937073	130937200
ENSE00001263195	130943351	130943462
ENSE00001263208	130990393	130990542
ENSE00002098422	131039374	131040909
ENSE00003576627	130951868	130951998
ENSE00003790708	130903772	130904042

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 86.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8905 / max 105.4209, expressed in 1717 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
27342	9.8905	1717
27341	1.0894	628
95035	0.5291	167
27340	0.3848	220
95036	0.3472	151
95034	0.0529	30
27338	0.0183	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	86.96	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	85.95	gold quality
caput epididymis	UBERON:0004358	81.62	gold quality
inferior olivary complex	UBERON:0002127	80.34	gold quality
corpus epididymis	UBERON:0004359	80.19	gold quality
lateral globus pallidus	UBERON:0002476	78.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.33	gold quality
pons	UBERON:0000988	77.41	gold quality
dorsal plus ventral thalamus	UBERON:0001897	77.31	gold quality
amygdala	UBERON:0001876	77.20	gold quality
cauda epididymis	UBERON:0004360	76.14	gold quality
medulla oblongata	UBERON:0001896	76.03	gold quality
prefrontal cortex	UBERON:0000451	76.02	gold quality
temporal lobe	UBERON:0001871	75.66	gold quality
cingulate cortex	UBERON:0003027	75.47	gold quality
anterior cingulate cortex	UBERON:0009835	75.25	gold quality
paraflocculus	UBERON:0005351	75.21	silver quality
hypothalamus	UBERON:0001898	74.68	gold quality
substantia nigra	UBERON:0002038	74.68	gold quality
midbrain	UBERON:0001891	74.59	gold quality
entorhinal cortex	UBERON:0002728	74.52	gold quality
globus pallidus	UBERON:0001875	74.47	gold quality
Ammon’s horn	UBERON:0001954	74.42	gold quality
medial globus pallidus	UBERON:0002477	74.23	gold quality
right frontal lobe	UBERON:0002810	74.23	gold quality
superior vestibular nucleus	UBERON:0007227	73.91	gold quality
primary visual cortex	UBERON:0002436	73.81	gold quality
neocortex	UBERON:0001950	73.64	gold quality
corpus callosum	UBERON:0002336	73.60	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	73.60	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 26)

• Fog protein is apically polarized and is both necessary and sufficient to drive apical myosin localization through a mechanism involving activation of myosin contractility with actin. (PMID:16123312)
• receptor tyrosine phosphatase PTP52F is a downstream component of the Fog signaling pathway in CNS neurons (PMID:17560973)
• we propose that Gprk2 attenuates and tunes Fog-Cta signaling to prevent apical constriction in lateral mesodermal cells and to support appropriate apical constriction in ventral mesodermal cells. (PMID:24026125)
• The mitochondria, through regulation of fusion and fission, function as downstream effectors and modulators of Fog signaling and Fog-dependent cell shape change. (PMID:24101729)
• G protein-coupled receptor mist and its ligand fog have roles in regulating epithelial morphogenesis (PMID:24222713)
• Both genes are expressed and required for mesoderm invagination in the fruit fly Drosophila melanogaster but do not appear during mesoderm ingression of the midge Chironomus riparius. (PMID:27685537)
• Drosophila Fog/Cta and T48 pathways have overlapping and distinct contributions to mesoderm invagination. (PMID:38536475)
• Cyclic AMP compartmentation due to increased cAMP-phosphodiesterase activity in transgenic mice expressing human adenylyl cyclase type 8. (PMID:12890691)
• A direct interaction between the N terminus of adenylyl cyclase AC8 and the catalytic subunit of protein phosphatase 2A was shown (PMID:16258073)
• recruited CaM is used by the C terminus of AC8 to mediate Ca2+ stimulation (PMID:16613843)
• Fully differentiated human airway epithelial cells in culture are shown to express calcium-stimulated transmembrane adenylyl cyclase (tmAC) isoforms (types 1, 3, and 8) by reverse transcription polymerase chain reaction. (PMID:17586501)
• Redundant cyclase activity maintains the balance between presynaptically silent and active synapses, but AC8 plays an mportant role in resetting the balance of active to silent synapses after adaptation to strong activity. (PMID:18480272)
• Distinct mechanisms of regulation by Ca2+/calmodulin of type 1 and 8 adenylyl cyclases support their different physiological roles. (PMID:19029295)
• Colocalizes with Orai1 and stromal interaction molecule 1 (STIM1) at the plasma membrane in lipid rafts (PMID:19171672)
• The data of this study suggested that Adcy8 might encode a translational behavioral endophenotype of bipolar disorder. (PMID:19691954)
• Data reveal that an association of the Ca(2+)-stimulable AC8 with AKAP79/150 that limits the sensitivity of AC8 to intracellular Ca(2+) events. (PMID:20410303)
• Ca2+ entry increase was accompanied by red cell aggregation rise, while adenylyl cyclase-cAMP system stimulation led to red cell deformability increase and its aggregation lowered. (PMID:20675917)
• cAMP-mediated pathways are modelled by glucose, and downregulation of the calcium-sensitive ADCY8 plays a central role herein, including signalling via the GLP1R. (PMID:21046358)
• Orai1 and AC8 binding mediates dynamic interplay between Ca2+ and cAMP signaling (PMID:22494970)
• The adenylate cyclase 8 plays a major role in cAMP production. (PMID:23200849)
• Polymorphisms ADCY8 are associated with an alcohol-dependent phenotype in females, which is distinguished by comorbid signs of depression. (PMID:23278386)
• ADCY8 is integral for long-term potentiation and synaptic plasticity and is implicated in fear-related learning and memory. (PMID:24677629)
• ADCY8 is required for the physiological activation of glucose-induced signalling pathways in beta cells, for glucose tolerance and for hypothalamic adaptation to a high-fat diet via regulation of islet insulin secretion. (PMID:25403481)
• Our results provide evidence for new loci influencing abdominal visceral (BBS9, ADCY8, KCNK9) and subcutaneous (MLLT10/DNAJC1/EBLN1) fat, and confirmed a locus (THNSL2) previously reported to be associated with abdominal fat in women (PMID:26480920)
• Results show that promoter hypermethylation of ADCY8, CDH8, and ZNF582 are correlated with high-grade squamous intraepithelial lesion. (PMID:27651839)
• Colocalization of caveolin1 and adenylyl cyclase 8 in lipid rafts depends on the cytoskeleton. (PMID:30746562)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adcy8	ENSDARG00000031783
mus_musculus	Adcy8	ENSMUSG00000022376
rattus_norvegicus	Adcy8	ENSRNOG00000004890

Paralogs (17): GUCY1B1 (ENSG00000061918), GUCY2C (ENSG00000070019), ADCY2 (ENSG00000078295), GUCY2F (ENSG00000101890), NPR3 (ENSG00000113389), ADCY7 (ENSG00000121281), ADCY4 (ENSG00000129467), GUCY2D (ENSG00000132518), ADCY3 (ENSG00000138031), GUCY1A2 (ENSG00000152402), NPR2 (ENSG00000159899), ADCY9 (ENSG00000162104), GUCY1A1 (ENSG00000164116), ADCY1 (ENSG00000164742), NPR1 (ENSG00000169418), ADCY5 (ENSG00000173175), ADCY6 (ENSG00000174233)

Protein

Protein identifiers

Adenylate cyclase type 8 — P40145 (reviewed: P40145)

Alternative names: ATP pyrophosphate-lyase 8, Adenylate cyclase type VIII, Adenylyl cyclase 8, Ca(2+)/calmodulin-activated adenylyl cyclase

All UniProt accessions (4): P40145, A0A0K0K1K3, E5RFR2, E7EVL1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the formation of cAMP in response to calcium entry leadings to cAMP signaling activation that affect processes suche as synaptic plasticity and insulin secretion. Plays a role in many brain functions, such as learning, memory, drug addiction, and anxiety modulation through regulation of synaptic plasticity by modulating long-term memory and long-term potentiation (LTP) through CREB transcription factor activity modulation. Plays a central role in insulin secretion by controlling glucose homeostasis through glucagon-like peptide 1 and glucose signaling pathway and maintains insulin secretion through calcium-dependent PKA activation leading to vesicle pool replenishment. Also, allows PTGER3 to induce potentiation of PTGER4-mediated PLA2 secretion by switching from a negative to a positive regulation, during the IL1B induced-dedifferentiation of smooth muscle cells.

Subunit / interactions. Homodimer; via transmembrane domain. Monomer. Heterodimer. Oligemer; via transmembrane domain. Interacts with PRKAR2A and AKAP5; inhibits adenylate cyclase activity through PKA phosphorylation. Interacts with PPP2CA and PPP2R1A; does not mediate the inhibitory effects of PKA on adenylate cyclase activity; interaction is dependent of catalytically active PPP2CA; antagonizes interaction with calmodulin. Interacts with AKAP5 (palmitoylated form); promotes the phosphorylation of ADCY8 after store-operated calcium entry (SOCE) stimulation at membrane raft. Interacts with ORAI1; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events. Interacts with STIM1. Interacts with actin; interaction is calcium independent; interaction is affected by calcium-calmodulin; interaction controls the distribution and regulation of ADCY8. Interacts with calmodulin; at rest, interacts via N-terminal domain; upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain forming an autoinhibitory complex; fully calcium-saturated calmodulin leaves the N-terminal domain, binding solely to the C-terminal domain leading to dissociation of autoinhibitory complex and resulting in activation of adenylate cyclase; antagonizes interaction with PPP2CA; interaction is calcium dependent. Interacts with PPP2R5D.

Subcellular location. Cell membrane. Basolateral cell membrane. Apical cell membrane. Synapse. Cell projection. Dendrite. Axon. Presynaptic cell membrane. Postsynaptic density. Membrane raft. Membrane. Coated pit. Cytoplasmic vesicle. Clathrin-coated vesicle membrane. Caveola.

Tissue specificity. Detected in brain cortex. Expressed in islet.

Post-translational modifications. Phosphorylated by PKA; mediates inhibition of adenylate cyclase activity at membrane raft; does not influence either CALM1 or PPP2CA interaction with ADCY8. N-glycosylated; N-glycosylation is responsible for raft-targeting; is not necessary for CCE-stimulated adenylate cyclase activity.

Activity regulation. At rest, the N- and C-terminal domains interact, as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain. Upon a calcium rise, calmodulin becomes calcium-saturated and subsequently binds to the C-terminal domain. Fully calcium-saturated calmodulin then leaves the N-terminal domain, binding solely to the C-terminal domain, and the whole autoinhibitory complex dissociates, resulting in activation of adenylate cyclase. As local calcium concentrations decrease, the calmodulin becomes calcium free and binds once more to the N-terminal domain, whereupon the whole system returns to rest with the re-association of the autoinhibitory complex. In non-excitable cells, activated by capacitative calcium entry (CCE) through store-operated channels, namely through interaction with ORAI1 and STIM1; membrane raft and caveolae localization and membrane integrity are indispensable. CCE-mediated adenylate cyclase activity is decreased by AKAP5 and AKAP7. CCE-mediated adenylate cyclase activity is up-regulated by AKAP9 and the mitochondrially targeted AKAP1. In excitable cells, activated during membrane depolarization through L-type voltage-gated calcium channels (VGCC), leading to calcium entry; the L-type alpha subunit is sufficient. Activated via stimulation of the GLP1R. Synergistically activated by calcium/calmodulin and GNAS. Stimulated by forskolin. Inhibited by PKA directly bound to AKAP5 at membrane raft. Inhibition by acute activation of OPRM1 and activation by chronic activation of OPRM1 is mediated by pertussis toxin-sensitive G(i) and G(o) G alpha proteins and G beta-gamma dimer. Activity is inhibited by G beta-gamma dimer.

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. The two transmembrane clusters are necessary and suficient for the plasma membrane targeting and oligomers assembly. The N-terminal and C-terminal domains interact at rest as part of a larger autoinhibitory complex, with calmodulin pre-associated at the N-terminal domain; the binding is specifically inhibited by fully calcium-saturated calmodulin, resulting in activation of AC8.

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

RefSeq proteins (1): NP_001106* (*=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

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (50 total): transmembrane region 12, binding site 12, region of interest 6, site 5, topological domain 3, modified residue 3, glycosylation site 3, short sequence motif 2, sequence variant 2, chain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P40145-F1	71.82	0.23

Functional residue map

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

Catalytic / active sites (5): 1199 (essential for autoinhibition maintenance by promoting interaction of the n and c termini); 1200 (essential for autoinhibition maintenance); 1203 (essential for autoinhibition maintenance by promoting interaction of the n and c termini); 1205 (essential for calm1 interaction); 1207 (essential for calm1 interaction)

Ligand- & substrate-binding residues (12): 419–424; 419; 419; 420; 461–463; 463; 463; 507; 1034; 1109–1111; 1116–1120; 1156

Post-translational modifications (3): 55, 614, 624

Glycosylation sites (3): 817, 821, 888

Function

Pathways and Gene Ontology

Reactome pathways

51 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-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
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-442720	CREB1 phosphorylation through the activation of Adenylate Cyclase
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

MSigDB gene sets: 612 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, ATF_B, GOBP_MEMORY, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_SINGLE_FERTILIZATION, FXR_IR1_Q6, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, CCAWYNNGAAR_UNKNOWN, MORF_MSH3, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID

GO Biological Process (34): renal water homeostasis (GO:0003091), cAMP biosynthetic process (GO:0006171), signal transduction (GO:0007165), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), positive regulation of cytosolic calcium ion concentration (GO:0007204), learning or memory (GO:0007611), memory (GO:0007613), long-term memory (GO:0007616), locomotory behavior (GO:0007626), glucose mediated signaling pathway (GO:0010255), positive regulation of synaptic plasticity (GO:0031915), positive regulation of insulin secretion (GO:0032024), obsolete positive regulation of CREB transcription factor activity (GO:0032793), activation of protein kinase A activity (GO:0034199), intracellular signal transduction (GO:0035556), positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), G protein-coupled opioid receptor signaling pathway (GO:0038003), glucose homeostasis (GO:0042593), protein complex oligomerization (GO:0051259), protein homooligomerization (GO:0051260), regulation of cytosolic calcium ion concentration (GO:0051480), cellular response to calcium ion (GO:0071277), cellular response to morphine (GO:0071315), cellular response to glucose stimulus (GO:0071333), cellular response to glucagon stimulus (GO:0071377), regulation of cellular response to stress (GO:0080135), vascular endothelial cell response to laminar fluid shear stress (GO:0097700), neuroinflammatory response (GO:0150076), positive regulation of long-term synaptic potentiation (GO:1900273), positive regulation of long-term synaptic depression (GO:1900454), cellular response to forskolin (GO:1904322), cyclic nucleotide biosynthetic process (GO:0009190), regulation of insulin secretion (GO:0050796), modulation of chemical synaptic transmission (GO:0050804)

GO Molecular Function (13): actin binding (GO:0003779), adenylate cyclase activity (GO:0004016), calmodulin binding (GO:0005516), ATP binding (GO:0005524), calcium- and calmodulin-responsive adenylate cyclase activity (GO:0008294), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein heterodimerization activity (GO:0046982), protein dimerization activity (GO:0046983), protein phosphatase 2A binding (GO:0051721), nucleotide binding (GO:0000166), lyase activity (GO:0016829), phosphorus-oxygen lyase activity (GO:0016849)

GO Cellular Component (23): plasma membrane (GO:0005886), caveola (GO:0005901), clathrin-coated pit (GO:0005905), postsynaptic density (GO:0014069), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), axon (GO:0030424), dendrite (GO:0030425), clathrin-coated vesicle membrane (GO:0030665), neuronal cell body membrane (GO:0032809), presynaptic membrane (GO:0042734), plasma membrane raft (GO:0044853), membrane raft (GO:0045121), presynaptic active zone (GO:0048786), excitatory synapse (GO:0060076), Schaffer collateral - CA1 synapse (GO:0098685), hippocampal mossy fiber to CA3 synapse (GO:0098686), glutamatergic synapse (GO:0098978), actin cytoskeleton (GO:0015629), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-17 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
Regulation of insulin secretion	1
Aquaporin-mediated transport	1
Post NMDA receptor activation events	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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
plasma membrane region	3
synapse	3
behavior	2
protein binding	2
protein dimerization activity	2
membrane	2
cellular anatomical structure	2
neuron projection	2
presynapse	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
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
regulation of biological quality	1
cognition	1
learning or memory	1
memory	1
hexose mediated signaling	1
cellular response to glucose stimulus	1
regulation of synaptic plasticity	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
activation of protein kinase activity	1
intracellular anatomical structure	1
signal transduction	1
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
G protein-coupled receptor signaling pathway	1
carbohydrate homeostasis	1

Protein interactions and networks

STRING

2504 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADCY8	CALM1	P02593	957
ADCY8	CALML3	P27482	934
ADCY8	CALML4	Q96GE6	934
ADCY8	CALML5	Q9NZT1	934
ADCY8	CALML6	Q8TD86	931
ADCY8	GRM3	Q14832	830
ADCY8	GRIN2A	Q12879	829
ADCY8	PRKACG	P22612	819
ADCY8	CAMK2G	Q13555	817
ADCY8	GRIN2B	Q13224	756
ADCY8	PRKCA	P17252	754
ADCY8	DNAJC27	Q9NZQ0	728
ADCY8	PRKACA	P17612	709
ADCY8	RAPGEF4	Q8WZA2	691
ADCY8	PROKR1	Q8TCW9	651

IntAct

6 interactions, top by confidence:

A	B	Type	Score
CFTR	SNHG32	psi-mi:“MI:0914”(association)	0.350
PHKG2	N4BP1	psi-mi:“MI:0914”(association)	0.350
CACNA1C	DISP2	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
ADCY8	STX7	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): ADCY8 (Synthetic Lethality), C1orf43 (Affinity Capture-MS), PEX16 (Affinity Capture-MS), LGALS3 (Affinity Capture-MS), PLD6 (Affinity Capture-MS), FITM2 (Affinity Capture-MS), LEMD2 (Affinity Capture-MS), PLAA (Affinity Capture-MS), PTPLB (Affinity Capture-MS), STX7 (Affinity Capture-MS), ANKMY2 (Affinity Capture-MS), OMA1 (Affinity Capture-MS), ADCY8 (Affinity Capture-MS), ADCY8 (Protein-peptide), ADCY8 (Protein-peptide)

ESM2 similar proteins: A0A1D5PXA5, A0A1S4GYH6, A1Z7G7, B3MFV7, B3N8M1, B4GD14, B4HS00, B4J780, B4KMZ1, B4LNA8, B4P3A0, G5EFJ9, O01635, O35607, O54852, O73925, P22815, P30432, P34410, P40145, P40146, P48994, P51787, P57789, P79701, P91682, P97414, P97490, Q09274, Q10025, Q13873, Q19187, Q21974, Q24738, Q292N4, Q86GV3, Q95TU8, Q96L42, Q9EPK8, Q9ER47

Diamond homologs: A0A0U1RPR8, A8WPG9, A8XQC7, B1Q257, H2L002, N1NVB7, O02298, O02740, O16544, O19179, O54865, O60503, O62026, O62179, O75343, O88444, O95622, P0A4Y1, P16066, P16068, P18293, P19686, P19687, P19754, P20595, P22717, P23897, P25092, P26769, P26770, P30803, P30804, P33402, P40144, P40145, P40146, P51828, P51829, P51830, P51839

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
NF1	up-regulates	ADCY8
ADCY8	“up-regulates quantity”	“3’,5’-cyclic AMP”	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	156
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
144139	GRCh38/hg38 8q24.21-24.3(chr8:130115518-141228210)x3	Pathogenic
2578018	GRCh37/hg19 8q24.21-24.3(chr8:131138343-143473913)	Pathogenic
3063053	GRCh37/hg19 8q24.11-24.22(chr8:118071721-132774256)x1	Pathogenic
57119	GRCh38/hg38 8q24.21-24.22(chr8:129176782-134170188)x1	Pathogenic
687747	GRCh37/hg19 8q24.13-24.22(chr8:124120772-135265846)x1	Pathogenic
815167	GRCh37/hg19 8q24.13-24.3(chr8:126892814-143750028)x1	Pathogenic
394662	GRCh37/hg19 8q24.21-24.22(chr8:128295596-133200773)x1	Likely pathogenic

SpliceAI

3708 predictions. Top by Δscore:

Variant	Effect	Δscore
8:130780875:TGC:T	acceptor_gain	1.0000
8:130780878:C:CC	acceptor_gain	1.0000
8:130780879:T:A	acceptor_loss	1.0000
8:130783684:TACTC:T	donor_loss	1.0000
8:130783685:AC:A	donor_loss	1.0000
8:130783686:CTC:C	donor_loss	1.0000
8:130783687:T:TC	donor_loss	1.0000
8:130783688:C:CG	donor_loss	1.0000
8:130783689:A:AC	donor_gain	1.0000
8:130783689:ACCA:A	donor_loss	1.0000
8:130783690:C:CT	donor_gain	1.0000
8:130783690:CCAAT:C	donor_gain	1.0000
8:130783801:CATTG:C	acceptor_gain	1.0000
8:130783802:ATTG:A	acceptor_gain	1.0000
8:130783803:TTG:T	acceptor_gain	1.0000
8:130783804:TG:T	acceptor_gain	1.0000
8:130783805:GC:G	acceptor_loss	1.0000
8:130783806:C:CC	acceptor_gain	1.0000
8:130783806:CTG:C	acceptor_loss	1.0000
8:130783807:T:G	acceptor_loss	1.0000
8:130783812:C:CT	acceptor_gain	1.0000
8:130783816:CA:C	acceptor_gain	1.0000
8:130783817:A:C	acceptor_gain	1.0000
8:130785377:CTTTA:C	donor_loss	1.0000
8:130785379:TTA:T	donor_loss	1.0000
8:130785380:TAC:T	donor_loss	1.0000
8:130785476:C:CC	acceptor_gain	1.0000
8:130814064:CTCA:C	donor_loss	1.0000
8:130814065:TCAC:T	donor_loss	1.0000
8:130814066:CA:C	donor_loss	1.0000

AlphaMissense

8182 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:130780550:A:G	L1199P	1.000
8:130780727:A:G	L1140P	1.000
8:130780751:A:T	V1132D	1.000
8:130780773:C:A	G1125W	1.000
8:130780787:C:G	R1120P	1.000
8:130780789:G:C	S1119R	1.000
8:130780789:G:T	S1119R	1.000
8:130780791:T:G	S1119R	1.000
8:130780793:G:T	A1118E	1.000
8:130780798:G:C	N1116K	1.000
8:130780798:G:T	N1116K	1.000
8:130780811:C:A	G1112V	1.000
8:130780812:C:G	G1112R	1.000
8:130780813:C:A	W1111C	1.000
8:130780813:C:G	W1111C	1.000
8:130780815:A:G	W1111R	1.000
8:130780815:A:T	W1111R	1.000
8:130780817:A:T	I1110N	1.000
8:130780819:G:C	D1109E	1.000
8:130780819:G:T	D1109E	1.000
8:130780820:T:A	D1109V	1.000
8:130780820:T:C	D1109G	1.000
8:130780820:T:G	D1109A	1.000
8:130780821:C:G	D1109H	1.000
8:130780823:T:C	Y1108C	1.000
8:130780823:T:G	Y1108S	1.000
8:130780824:A:C	Y1108D	1.000
8:130780824:A:G	Y1108H	1.000
8:130780829:G:T	P1106Q	1.000
8:130780830:G:A	P1106S	1.000

dbSNP variants (sampled 300 via entrez): RS1000002124 (8:130835680 T>G), RS1000021955 (8:131016617 G>A), RS1000035821 (8:131041153 T>C), RS1000042520 (8:130926279 A>G), RS1000051086 (8:130884195 T>C), RS1000060126 (8:130830726 A>C), RS1000069071 (8:130831967 C>T), RS1000103463 (8:130920322 A>G), RS1000107710 (8:130879434 A>G), RS1000124220 (8:130872433 C>T), RS1000126924 (8:130795001 A>T), RS1000127339 (8:130986534 T>A), RS1000148074 (8:130825247 A>G), RS1000148391 (8:131006049 C>A,G), RS1000148999 (8:130932399 G>A)

Disease associations

OMIM: gene MIM:103070 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): distal trisomy 8q (MONDO:0019882)

Orphanet (1): Distal duplication 8q syndrome (Orphanet:96100)

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000892_5	Total ventricular volume (Alzheimer’s disease interaction)	2.000000e-06
GCST002401_5	Post-traumatic stress disorder	6.000000e-07
GCST002408_12	Response to methotrexate in juvenile idiopathic arthritis	6.000000e-06
GCST002408_7	Response to methotrexate in juvenile idiopathic arthritis	5.000000e-07
GCST002875_86	Diisocyanate-induced asthma	1.000000e-06
GCST003171_2	Visceral adipose tissue	3.000000e-07
GCST003453_11	Chronotype	1.000000e-06
GCST003454_9	Morning vs. evening chronotype	3.000000e-08
GCST004749_21	Lung cancer in ever smokers	8.000000e-06
GCST006904_2	Cerebral amyloid deposition (PET imaging)	5.000000e-07
GCST008394_3	Mild to moderate chronic kidney disease	2.000000e-07
GCST009153_10	Adverse response to chemotherapy (amenorrhea) in breast cancer	1.000000e-06
GCST011743_59	HDL cholesterol levels in HIV infection	8.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2097167 (PROTEIN FAMILY), CHEMBL2960 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 40,599 (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
CHEMBL52606	COLFORSIN	2	40,599

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Adenylyl cyclases (ACs)

ChEMBL bioactivities

77 potent at pChembl≥5 of 102 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	IC50	90	nM	CHEMBL6172918
7.03	EC50	93.7	nM	COLFORSIN
7.00	IC50	100	nM	CHEMBL6162018
7.00	IC50	100	nM	CHEMBL6167997
6.98	EC50	105.2	nM	CHEMBL4644318
6.96	Ki	110	nM	CHEMBL62412
6.89	IC50	130	nM	CHEMBL6159787
6.84	Ki	144	nM	CHEMBL64475
6.59	Ki	254	nM	CHEMBL62444
6.52	Ki	300	nM	CHEMBL62892
6.50	Ki	317	nM	CHEMBL64646
6.42	IC50	380	nM	CHEMBL5190252
6.24	IC50	570	nM	CHEMBL5170189
6.21	Ki	610	nM	CHEMBL418468
6.16	IC50	700	nM	CHEMBL5195432
6.15	IC50	710	nM	CHEMBL5182403
6.11	IC50	780	nM	CHEMBL5178772
6.09	IC50	810	nM	CHEMBL6163275
6.00	IC50	1000	nM	CHEMBL5205425
6.00	IC50	1000	nM	CHEMBL5187427
6.00	Ki	1000	nM	CHEMBL64955
5.92	IC50	1200	nM	CHEMBL2098167
5.89	IC50	1300	nM	CHEMBL5197376
5.89	IC50	1300	nM	CHEMBL5197311
5.85	IC50	1400	nM	CHEMBL4456548
5.80	IC50	1600	nM	CHEMBL5186455
5.77	IC50	1700	nM	CHEMBL5178349
5.76	IC50	1730	nM	CHEMBL6170825
5.72	IC50	1900	nM	CHEMBL5187824
5.72	IC50	1900	nM	CHEMBL5186344
5.70	IC50	2000	nM	CHEMBL4467742
5.68	IC50	2100	nM	CHEMBL5199983
5.62	IC50	2400	nM	CHEMBL4585588
5.60	IC50	2500	nM	CHEMBL5203054

PubChem BioAssay actives

68 with measured affinity, of 242 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
[(3R,4aR,5S,6S,6aS,10S,10aR,10bS)-3-ethenyl-6,10,10b-trihydroxy-3,4a,7,7,10a-pentamethyl-1-oxo-5,6,6a,8,9,10-hexahydro-2H-benzo[f]chromen-5-yl] acetate	1646831: Agonist activity at recombinant human AC8 expressed in human HEK293 cells assessed as fold increase in cAMP level by LANCE Ultra cAMP Detection kit method	ec50	0.0937	uM
ethyl 3-[(2,4-dichlorophenyl)methyl]-2-oxo-1H-indole-3-carboxylate	1646831: Agonist activity at recombinant human AC8 expressed in human HEK293 cells assessed as fold increase in cAMP level by LANCE Ultra cAMP Detection kit method	ec50	0.1052	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
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
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
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
3-tert-butyl-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	0.3800	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3-phenylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	0.5700	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
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-4-phenylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	0.7000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3,4-dimethylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	0.7100	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-4-fluorobenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	0.7800	uM
3-chloro-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.0000	uM
4-(dimethylamino)-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.0000	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
4-tert-butyl-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.2000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3-(trifluoromethyl)benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.3000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3-methylsulfanylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.3000	uM
N-(5-cyclohexyl-1,3,4-oxadiazol-2-yl)-3-phenylbenzamide	1586056: Inhibition of human AC8 expressed in HEK293 cells assessed as decrease in A23187-stimulated cAMP accumulation preincubated for 30 mins followed by A23187 stimulation and measured after 1 hr by fluorescence assay	ic50	1.4000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3-fluorobenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.6000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3,5-dimethylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.7000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-2-fluorobenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.9000	uM
3-cyclopropyl-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	1.9000	uM
4-ethyl-N-[5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]benzamide	1586056: Inhibition of human AC8 expressed in HEK293 cells assessed as decrease in A23187-stimulated cAMP accumulation preincubated for 30 mins followed by A23187 stimulation and measured after 1 hr by fluorescence assay	ic50	2.0000	uM
3-bromo-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	2.1000	uM
3-methyl-N-[5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]-5-(trifluoromethyl)benzamide	1586056: Inhibition of human AC8 expressed in HEK293 cells assessed as decrease in A23187-stimulated cAMP accumulation preincubated for 30 mins followed by A23187 stimulation and measured after 1 hr by fluorescence assay	ic50	2.4000	uM
4-chloro-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	2.5000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3-propan-2-ylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	2.6000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-3-methylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	2.7000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]pyridine-2-carboxamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	2.8000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-2-fluoro-5-methylbenzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	3.4000	uM
N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]-2-(2-fluorophenyl)acetamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	3.4000	uM
3-ethyl-N-[2-(4-ethyl-6-oxo-1H-pyrimidin-2-yl)-5-methylpyrazol-3-yl]benzamide	1904801: Inhibition of Ca2+/ CAM stimulated human AC8 activity expressed in AC3 and AC6-knockout HEK293 cells assessed as A23187 stimulated cAMP accumulation incubated for 30 mins followed by A2318 stimulation in presence of IBMX for 1 hr by HTRF assay	ic50	3.5000	uM
4-chloro-N-[5-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,4-oxadiazol-2-yl]benzamide	1586056: Inhibition of human AC8 expressed in HEK293 cells assessed as decrease in A23187-stimulated cAMP accumulation preincubated for 30 mins followed by A23187 stimulation and measured after 1 hr by fluorescence assay	ic50	3.6000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	4
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
terbufos	increases methylation	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation, affects methylation	1
Doxorubicin	increases expression	1
Fonofos	increases methylation	1
Lead	affects expression	1
Oxygen	increases expression	1
Parathion	increases methylation	1
Cyclosporine	decreases expression	1
Particulate Matter	increases abundance, increases expression	1

ChEMBL screening assays

31 unique, capped per target: 28 binding, 2 functional, 1 admet

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
CHEMBL4685442	ADMET	Agonist activity at recombinant human AC8 expressed in HEK293 cells assessed as increase in cAMP level at 50 uM measured after 30 mins by LANCE Ultra cAMP Detection kit method	The discovery, design and synthesis of potent agonists of adenylyl cyclase type 2 by virtual screening combining biological evaluation. — Eur J Med Chem

Clinical trials (associated diseases)

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