PDE8B

Summary

PDE8B (phosphodiesterase 8B, HGNC:8794) is a protein-coding gene on chromosome 5q13.3, encoding High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8B (O95263). Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes.

The protein encoded by this gene is a cyclic nucleotide phosphodiesterase (PDE) that catalyzes the hydrolysis of the second messenger cAMP. The encoded protein, which does not hydrolyze cGMP, is resistant to several PDE inhibitors. Defects in this gene are a cause of autosomal dominant striatal degeneration (ADSD). Several transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8622 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant striatal neurodegeneration type 1 (Strong, GenCC) — +4 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 360 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• MANE Select transcript: NM_003719

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8794
Approved symbol	PDE8B
Name	phosphodiesterase 8B
Location	5q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000113231
Ensembl biotype	protein_coding
OMIM	603390
Entrez	8622

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000264917, ENST00000333194, ENST00000340978, ENST00000342343, ENST00000346042, ENST00000502945, ENST00000503963, ENST00000505283, ENST00000505926

RefSeq mRNA: 18 — MANE Select: NM_003719 NM_001029851, NM_001029852, NM_001029853, NM_001029854, NM_001349748, NM_001349749, NM_001349751, NM_001376063, NM_001376064, NM_001376065, NM_001376066, NM_001376069, NM_001376070, NM_001376071, NM_001376073, NM_001376074, NM_001376075, NM_003719

CCDS: CCDS34190, CCDS34191, CCDS34192, CCDS34193, CCDS4037

Canonical transcript exons

ENST00000264917 — 22 exons

Exon	Start	End
ENSE00000000337	77210680	77211264
ENSE00000754959	77349419	77349559
ENSE00000754980	77404720	77404797
ENSE00000971774	77325539	77325729
ENSE00001082788	77421821	77421988
ENSE00001082791	77407381	77407457
ENSE00001082792	77408893	77409057
ENSE00001082793	77400248	77400290
ENSE00001082794	77419767	77419887
ENSE00001082795	77413111	77413309
ENSE00001082796	77418229	77418446
ENSE00001082797	77353346	77353406
ENSE00001082798	77425767	77425896
ENSE00001082799	77344853	77344931
ENSE00002081311	77426445	77428256
ENSE00002484561	77351065	77351153
ENSE00003503397	77328998	77329057
ENSE00003523631	77311994	77312053
ENSE00003577001	77411676	77411721
ENSE00003633026	77337227	77337315
ENSE00003659724	77412100	77412235
ENSE00003789102	77331402	77331459

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 97.03.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left lobe of thyroid gland	UBERON:0001120	97.03	gold quality
right lobe of thyroid gland	UBERON:0001119	96.99	gold quality
thyroid gland	UBERON:0002046	95.28	gold quality
anterior cingulate cortex	UBERON:0009835	90.55	gold quality
descending thoracic aorta	UBERON:0002345	89.86	gold quality
left uterine tube	UBERON:0001303	89.62	gold quality
thoracic aorta	UBERON:0001515	89.31	gold quality
ascending aorta	UBERON:0001496	89.19	gold quality
right frontal lobe	UBERON:0002810	89.15	gold quality
right atrium auricular region	UBERON:0006631	88.99	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.80	gold quality
body of uterus	UBERON:0009853	88.44	gold quality
prefrontal cortex	UBERON:0000451	87.80	gold quality
cardiac atrium	UBERON:0002081	87.76	gold quality
hypothalamus	UBERON:0001898	87.22	gold quality
smooth muscle tissue	UBERON:0001135	86.97	gold quality
right uterine tube	UBERON:0001302	86.36	gold quality
putamen	UBERON:0001874	86.35	gold quality
caudate nucleus	UBERON:0001873	86.17	gold quality
endocervix	UBERON:0000458	86.16	gold quality
amygdala	UBERON:0001876	85.98	gold quality
nucleus accumbens	UBERON:0001882	85.89	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.89	gold quality
aorta	UBERON:0000947	85.68	gold quality
islet of Langerhans	UBERON:0000006	84.68	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.23	gold quality
omental fat pad	UBERON:0010414	83.93	gold quality
peritoneum	UBERON:0002358	83.81	gold quality
neocortex	UBERON:0001950	83.51	gold quality
ventricular zone	UBERON:0003053	83.49	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.82
E-HCAD-35	yes	6.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

122 targeting PDE8B, 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-4425	100.00	67.59	1049
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Literature-anchored findings (GeneRIF, showing 24)

• selective usage of exons produces three different PDE8B variants that exhibit a tissue-specific expression pattern (PMID:12372422)
• Comparison of enzymatic characterization and gene organization of PDE8B and PDE8A. (PMID:12681444)
• In Alzheimer’s disease brains we found that PDE8B was the only PDE isozyme showing a significant increase, in cortical areas and parts of the hippocampal formation, at Braak stages III-VI (PMID:12895443)
• PDE8B is another PDE gene linked to isolated micronodular adrenocortical disease; it is a candidate causative gene for other adrenocortical lesions linked to the cAMP signaling pathway and possibly for tumors in other tissues. (PMID:18431404)
• results suggest a primary effect of PDE8B variants on cAMP levels in the thyroid. This would affect production of T4 and T3 and feedback to alter TSH release by the pituitary. (PMID:18514160)
• Genetic variation in thyroid stimulating hormone levels in pregnancy associated with the PDE8B rs4704397 genotype has implications for the number of women treated for subclinical hypothyroidism under current guidelines (PMID:19820008)
• phosphodiesterase 8B has a role in autosomal-dominant striatal degeneration (PMID:20085714)
• Our analysis revealed separate segregation of an inactivating PDE8B allele from the high-TSH-allele and showed low TSH levels in persons who carry an inactivating PDE8B allele. These data suggest that PDE8B may be involved in regulation of TSH levels. (PMID:20373981)
• Common genetic variation in PDE8B is associated with reciprocal changes in thyroid hormone levels. (PMID:21317282)
• In obese children, PDE8B is associated with TSH; the interaction between adiposity and PDE8B on TSH is not synergistic, but follows an additive model. (PMID:22084153)
• PDE8B is another PDE gene in which variations may contribute to predisposition of adrenocortical tumours. (PMID:22335482)
• PDE8B gene polymorphisms may be correlated with hyperthyroxinemia in the Chinese Han population. (PMID:22781450)
• There is an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage. (PMID:23237535)
• rs4704397 in phosphodiesterase 8B is associated with thyrotropin and thyroid hormone concentrations (PMID:23272636)
• rs4704397 is associated with thyroid function, risk of MI, and body height. (PMID:23941514)
• A prevalence of the minor allele of PDE8B gene polymorphism associated with elevated serum levels of TSH was demonstrated in patients affected by sporadic nonautoimmune subclinical hypothyroidism. (PMID:24497218)
• Genetic variation of the PDE8B gene may be involved in the etiology of subclinical hypothyroidism in pregnant women. (PMID:25822812)
• a heterozygous nonsense mutation in the first exon of cyclic nucleotide phosphodiesterase 8B gene, which is predicted to disrupt all important functional domains of the cyclic nucleotide phosphodiesterase 8B protein, in two members of family with autosomal-dominant striatal degeneration (PMID:26769607)
• Single-nucleotide polymorphism in PDE8B gene is associated with Hashimoto’s thyroiditis. (PMID:28382505)
• replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation (PMID:28727628)
• Study shows that PDE8B may not play a major role in familial and early-onset Parkinson disease without distinctive lesions of the striatum on brain MRI in this Taiwanese population. (PMID:29909144)
• Clinical findings of autosomal-dominant striatal degeneration and PDE8B mutation screening in parkinsonism and related disorders. (PMID:31726290)
• cAMP-specific phosphodiesterase 8A and 8B isoforms are differentially expressed in human testis and Leydig cell tumor. (PMID:36277728)
• Single-cell transcriptomic analysis identifies downregulated phosphodiesterase 8B as a novel oncogene in IDH-mutant glioma. (PMID:38989284)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde8b	ENSDARG00000063706
mus_musculus	Pde8b	ENSMUSG00000021684
rattus_norvegicus	Pde8b	ENSRNOG00000010280
drosophila_melanogaster	Pde11	FBGN0085370
drosophila_melanogaster	Pde8	FBGN0266377
caenorhabditis_elegans		WBGENE00008443
caenorhabditis_elegans	pde-6	WBGENE00022389

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE10A (ENSG00000112541), PDE4D (ENSG00000113448), PDE1A (ENSG00000115252), PDE1B (ENSG00000123360), PDE11A (ENSG00000128655), PDE6A (ENSG00000132915), PDE6B (ENSG00000133256), PDE5A (ENSG00000138735), PDE3B (ENSG00000152270), PDE1C (ENSG00000154678), PDE9A (ENSG00000160191), PDE7B (ENSG00000171408), PDE3A (ENSG00000172572), PDE4B (ENSG00000184588), PDE2A (ENSG00000186642), PDE7A (ENSG00000205268)

Protein

Protein identifiers

High affinity cAMP-specific and IBMX-insensitive 3’,5’-cyclic phosphodiesterase 8B — O95263 (reviewed: O95263)

Alternative names: Cell proliferation-inducing gene 22 protein

All UniProt accessions (4): O95263, D6R9W0, D6RH10, D6RJD7

UniProt curated annotations — full annotation on UniProt →

Function. Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in specific signaling in the thyroid gland.

Tissue specificity. Abundantly expressed in the thyroid. Also very weakly expressed in brain, spinal cord and placenta. In the thyroid isoform 1 predominates, and isoforms 2 and 6 are also highly expressed. In the placenta isoforms 1 and 2 are expressed equally. In the brain isoform 2 predominates.

Disease relevance. Striatal degeneration, autosomal dominant 1 (ADSD1) [MIM:609161] A movement disorder affecting the striatal part of the basal ganglia and characterized by bradykinesia, dysarthria and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. The disease is caused by variants affecting the gene represented in this entry. Primary pigmented nodular adrenocortical disease 3 (PPNAD3) [MIM:614190] A rare bilateral adrenal defect causing ACTH-independent Cushing syndrome. Macroscopic appearance of the adrenals is characteristic with small pigmented micronodules observed in the cortex. Adrenal glands show overall normal size and weight, and multiple small yellow-to-dark brown nodules surrounded by a cortex with a uniform appearance. Microscopically, there are moderate diffuse cortical hyperplasia with mostly nonpigmented nodules, multiple capsular deficits and massive circumscribed and infiltrating extra-adrenal cortical excrescences with micronodules. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by dipyridimole. Insensitive to selective PDE inhibitors including rolipram and milrinone as well as to the non-selective inhibitor, IBMX. Unaffected by cGMP.

Cofactor. Binds 2 divalent metal cations per subunit. Site 1 may preferentially bind zinc ions, while site 2 has a preference for magnesium and/or manganese ions.

Domain organisation. Composed of a C-terminal catalytic domain containing two putative divalent metal sites and an N-terminal regulatory domain.

Pathway. Purine metabolism; 3’,5’-cyclic AMP degradation; AMP from 3’,5’-cyclic AMP: step 1/1.

Miscellaneous. Major isoform.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family. PDE8 subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
O95263-1	1, PDE8B1	yes
O95263-2	2, PDE8B2, PDE8B3
O95263-3	3, PDE8B3
O95263-4	4, PDE8B4
O95263-5	5
O95263-6	6, PDE8B2

RefSeq proteins (18): NP_001025022, NP_001025023, NP_001025024, NP_001025025, NP_001336677, NP_001336678, NP_001336680, NP_001362992, NP_001362993, NP_001362994, NP_001362995, NP_001362998, NP_001362999, NP_001363000, NP_001363002, NP_001363003, NP_001363004, NP_003710* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR002073	PDEase_catalytic_dom	Domain
IPR003607	HD/PDEase_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily
IPR057304	PDE8-like_REC_N	Domain

Pfam: PF00233, PF08629, PF13426, PF23198

Enzyme classification (BRENDA):

• EC 3.1.4.53 — 3’,5’-cyclic-AMP phosphodiesterase (BRENDA: 28 organisms, 62 substrates, 307 inhibitors, 60 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	—	34
3’,5’-CAMP	0.0003–0.5	13
CAMP	0.0001–0.191	9
CGMP	0.24–0.427	2
3’,5’-CGMP	1.6	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.124	1

Catalyzed reactions (Rhea), 1 shown:

• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (24 total): binding site 5, splice variant 5, region of interest 3, compositionally biased region 3, domain 2, modified residue 2, chain 1, sequence variant 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95263-F1	74.88	0.50

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 (1): 615 (proton donor)

Ligand- & substrate-binding residues (5): 619; 655; 656; 656; 781

Post-translational modifications (2): 517, 754

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 251 (showing top): BENPORATH_ES_WITH_H3K27ME3, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_NEGATIVE_REGULATION_OF_LIPID_METABOLIC_PROCESS, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GOBP_ASSOCIATIVE_LEARNING, GOBP_INSULIN_SECRETION, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, AAGCCAT_MIR135A_MIR135B, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_STEROID_METABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS

GO Biological Process (11): behavioral fear response (GO:0001662), cAMP catabolic process (GO:0006198), signal transduction (GO:0007165), visual learning (GO:0008542), operant conditioning (GO:0035106), neuromuscular process controlling balance (GO:0050885), negative regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0061179), positive regulation of ERK1 and ERK2 cascade (GO:0070374), negative regulation of steroid hormone biosynthetic process (GO:0090032), negative regulation of cAMP/PKA signal transduction (GO:0141162), negative regulation of insulin secretion (GO:0046676)

GO Molecular Function (6): 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
3’,5’-cyclic-nucleotide phosphodiesterase activity	2
behavioral defense response	1
fear response	1
purine ribonucleotide catabolic process	1
cyclic nucleotide catabolic process	1
cAMP metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
visual behavior	1
associative learning	1
learning	1
musculoskeletal movement	1
neuromuscular process	1
insulin secretion involved in cellular response to glucose stimulus	1
negative regulation of insulin secretion	1
negative regulation of response to stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
negative regulation of steroid biosynthetic process	1
negative regulation of hormone biosynthetic process	1
regulation of steroid hormone biosynthetic process	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
insulin secretion	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
cation binding	1
cyclic-nucleotide phosphodiesterase activity	1
phosphoric ester hydrolase activity	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE8B	CAPZB	P47756	852
PDE8B	PRKAR1A	P10644	843
PDE8B	ALDH7A1	P49419	754
PDE8B	ARMC5	Q96C12	719
PDE8B	GNAS	Q5JWF2	685
PDE8B	NUP62	P37198	621
PDE8B	POU1F1	P28069	566
PDE8B	FOXE1	O00358	511
PDE8B	FTL	P02792	493
PDE8B	GNAI2	P04899	491
PDE8B	MBIP	Q9NS73	490
PDE8B	PRDM11	Q9NQV5	479
PDE8B	CAPNS2	Q96L46	478
PDE8B	GPR65	Q8IYL9	455
PDE8B	PDE11A	Q9HCR9	454

IntAct

5 interactions, top by confidence:

A	B	Type	Score
steC	SCD	psi-mi:“MI:0914”(association)	0.460
PDE8B	PDE8A	psi-mi:“MI:0915”(physical association)	0.400
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (7): PDE8B (Affinity Capture-MS), PDE8B (Affinity Capture-MS), PDE8A (Affinity Capture-MS), PDE8B (Affinity Capture-MS), PDE8B (Proximity Label-MS), PDE8B (Cross-Linking-MS (XL-MS)), PDE8B (Affinity Capture-MS)

ESM2 similar proteins: A1A696, A1A698, A1A699, A2WYI4, A2XFW2, A2XL32, A2XLG5, A2XM23, B4YB07, E9Q4S1, I1MGE5, O49934, O95263, P06592, P06593, P06594, P06595, P14712, P14713, P14714, P15001, P19862, P25848, P29130, P30733, P33529, P33530, P34094, P36505, P42496, P42497, P42498, P42499, P42500, P55004, P55141, P93526, P93527, P93528, P93673

Diamond homologs: A0A077YBL0, B7YZV4, O18696, O60658, O88502, O89084, O95263, P06776, P12252, P14100, P14270, P14644, P14646, P27815, P30645, P54748, P54750, Q01061, Q01063, Q01064, Q01065, Q01066, Q07343, Q08493, Q08499, Q14123, Q3UEI1, Q61481, Q63421, Q64338, Q64395, Q6NNF2, Q86H13, Q8I5V4, Q8IRU4, Q9I7S6, Q9N2V9, Q9W4S9, Q9W4T4, B0G0Y8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	169
Likely benign	105
Benign	39

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1184901	NM_003719.5(PDE8B):c.94del (p.Val32fs)	Pathogenic
1184955	NM_003719.5(PDE8B):c.95T>C (p.Val32Ala)	Pathogenic
235862	NM_003719.5(PDE8B):c.79del (p.Arg27fs)	Pathogenic
2611068	NM_003719.5(PDE8B):c.328_329del (p.Thr110fs)	Pathogenic
2839265	NM_003719.5(PDE8B):c.1097del (p.Gly366fs)	Pathogenic
3233764	NM_003719.5(PDE8B):c.895G>T (p.Glu299Ter)	Pathogenic
6390	NM_003719.5(PDE8B):c.914A>C (p.His305Pro)	Pathogenic
6391	NM_003719.5(PDE8B):c.94_95delinsC (p.Val32fs)	Pathogenic
1012513	NM_003719.5(PDE8B):c.2331dup (p.Lys778Ter)	Likely pathogenic
235863	NM_003719.5(PDE8B):c.304G>T (p.Glu102Ter)	Likely pathogenic
2505562	NM_003719.5(PDE8B):c.1276C>T (p.Arg426Ter)	Likely pathogenic

SpliceAI

4371 predictions. Top by Δscore:

Variant	Effect	Δscore
5:77087109:ACC:A	donor_gain	1.0000
5:77087110:CCC:C	donor_gain	1.0000
5:77211265:G:GA	donor_loss	1.0000
5:77211266:T:A	donor_loss	1.0000
5:77325725:TGC:T	donor_gain	1.0000
5:77325727:CAGG:C	donor_loss	1.0000
5:77325728:AGGT:A	donor_loss	1.0000
5:77325729:GGTA:G	donor_loss	1.0000
5:77325730:G:A	donor_loss	1.0000
5:77325731:T:G	donor_loss	1.0000
5:77329054:GAGT:G	donor_gain	1.0000
5:77329056:GT:G	donor_gain	1.0000
5:77329058:G:GG	donor_gain	1.0000
5:77331457:AGGG:A	donor_loss	1.0000
5:77331458:GG:G	donor_gain	1.0000
5:77331458:GGGTA:G	donor_loss	1.0000
5:77331459:GG:G	donor_gain	1.0000
5:77331459:GGT:G	donor_loss	1.0000
5:77331460:G:C	donor_loss	1.0000
5:77331461:T:A	donor_loss	1.0000
5:77335520:GT:G	donor_gain	1.0000
5:77349390:ACT:A	acceptor_gain	1.0000
5:77349418:GTAT:G	acceptor_gain	1.0000
5:77407379:A:AG	acceptor_gain	1.0000
5:77407380:G:GG	acceptor_gain	1.0000
5:77407454:AAAGG:A	donor_loss	1.0000
5:77407455:AAG:A	donor_gain	1.0000
5:77407456:AG:A	donor_gain	1.0000
5:77407456:AGGTG:A	donor_loss	1.0000
5:77407457:GG:G	donor_gain	1.0000

AlphaMissense

5914 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:77344906:T:A	I284K	1.000
5:77349427:C:A	N295K	1.000
5:77349427:C:G	N295K	1.000
5:77351068:T:A	W341R	1.000
5:77351068:T:C	W341R	1.000
5:77353363:T:A	V375D	1.000
5:77407447:C:A	P452H	1.000
5:77407450:T:A	I453N	1.000
5:77408906:T:A	I460N	1.000
5:77408906:T:G	I460S	1.000
5:77408915:C:A	A463D	1.000
5:77408963:T:C	L479P	1.000
5:77408972:T:C	L482S	1.000
5:77408987:T:A	L487Q	1.000
5:77408987:T:C	L487P	1.000
5:77409038:T:C	L504P	1.000
5:77409050:T:C	L508P	1.000
5:77413196:T:A	W600R	1.000
5:77413196:T:C	W600R	1.000
5:77413238:T:C	Y614H	1.000
5:77413241:C:G	H615D	1.000
5:77413269:T:C	L624P	1.000
5:77418269:C:A	A651D	1.000
5:77418284:A:C	D656A	1.000
5:77418284:A:T	D656V	1.000
5:77418292:C:G	H659D	1.000
5:77418294:C:A	H659Q	1.000
5:77418294:C:G	H659Q	1.000
5:77418313:T:C	F666L	1.000
5:77418315:C:A	F666L	1.000

dbSNP variants (sampled 300 via entrez): RS1000013652 (5:77344786 T>G), RS1000014564 (5:77300120 A>G), RS1000037727 (5:77349348 G>A), RS1000051398 (5:77291423 G>A,T), RS1000065284 (5:77241560 C>T), RS1000066090 (5:77302042 T>C), RS1000070293 (5:77388398 G>A), RS1000083931 (5:77381724 G>T), RS1000093672 (5:77214380 G>A), RS1000098366 (5:77302377 A>C), RS1000137130 (5:77389496 A>G), RS1000141110 (5:77200668 T>C), RS1000147290 (5:77275914 G>A), RS1000152557 (5:77391414 G>A), RS1000181793 (5:77416601 T>C)

Disease associations

OMIM: gene MIM:603390 | disease phenotypes: MIM:609161, MIM:614190

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant striatal neurodegeneration type 1	Strong	Autosomal dominant
pigmented nodular adrenocortical disease, primary, 3	Strong	Autosomal dominant
primary pigmented nodular adrenocortical disease	Supportive	Autosomal dominant
striatal degeneration, autosomal dominant	Supportive	Autosomal dominant
schizophrenia	No Known Disease Relationship	Unknown

Mondo (5): autosomal dominant striatal neurodegeneration type 1 (MONDO:0012205), pigmented nodular adrenocortical disease, primary, 3 (MONDO:0013616), schizophrenia (MONDO:0005090), primary pigmented nodular adrenocortical disease (MONDO:0015999), striatal degeneration, autosomal dominant (MONDO:0000211)

Orphanet (2): Autosomal dominant striatal neurodegeneration (Orphanet:228169), OBSOLETE: Primary pigmented nodular adrenocortical disease (Orphanet:189439)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001260	Dysarthria
HP:0001288	Gait disturbance
HP:0001337	Tremor
HP:0001348	Brisk reflexes
HP:0001350	Slurred speech
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002075	Dysdiadochokinesis
HP:0002375	Hypokinesia
HP:0002395	Lower limb hyperreflexia
HP:0003118	Increased circulating cortisol level
HP:0003596	Middle age onset
HP:0003677	Slowly progressive
HP:0007039	Symmetric T2-signal increase with T1-signal decrease in the putamen
HP:0008221	Adrenal hyperplasia
HP:0040140	Degeneration of the striatum
HP:0100022	Abnormality of movement

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000199_1	Thyroid stimulating hormone levels	2.000000e-20
GCST001045_2	Caudate nucleus volume	2.000000e-07
GCST001474_10	Hypothyroidism	2.000000e-06
GCST001487_2	Thyroid function	3.000000e-27
GCST001856_28	Thyroid hormone levels	2.000000e-26
GCST001856_47	Thyroid hormone levels	6.000000e-24
GCST001856_48	Thyroid hormone levels	3.000000e-38
GCST002707_1	Serum thyroid-stimulating hormone levels	7.000000e-18
GCST003988_8	Hypothyroidism	1.000000e-23
GCST004061_3	Sjögren’s syndrome	8.000000e-06
GCST006897_2	Hyperthyroidism	4.000000e-22
GCST006898_4	Hypothyroidism	2.000000e-09
GCST007576_236	Chronotype	2.000000e-09
GCST007932_10	Medication use (thyroid preparations)	6.000000e-12
GCST008165_5	Thyroid stimulating hormone levels	4.000000e-33
GCST008165_6	Thyroid stimulating hormone levels	6.000000e-14
GCST010571_85	Autoimmune thyroid disease	3.000000e-12
GCST010653_19	Thyroid stimulating hormone levels	2.000000e-85
GCST010653_71	Thyroid stimulating hormone levels	1.000000e-269
GCST012796_3	Sjögren’s syndrome	3.000000e-06
GCST90002381_217	Eosinophil count	1.000000e-15
GCST90002382_110	Eosinophil percentage of white cells	1.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004296	thyroid function
EFO:0004730	hormone measurement
EFO:0008328	chronotype measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563783	Striatal Degeneration, Autosomal Dominant (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL2363066 (PROTEIN FAMILY), CHEMBL2363067 (PROTEIN FAMILY), CHEMBL4408 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphodiesterases, 3’,5’-cyclic nucleotide (PDEs)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
dipyridamole	Inhibition	4.3	pIC50

ChEMBL bioactivities

144 potent at pChembl≥5 of 146 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL5081214
9.92	IC50	0.12	nM	CHEMBL1780094
9.90	IC50	0.1259	nM	CHEMBL5080391
9.80	IC50	0.1585	nM	CHEMBL5087564
9.60	IC50	0.2512	nM	CHEMBL5094110
9.52	IC50	0.3	nM	CHEMBL5169811
9.50	IC50	0.3162	nM	CHEMBL5086895
9.50	IC50	0.3162	nM	CHEMBL5076558
9.05	IC50	0.9	nM	CHEMBL2070733
9.05	IC50	0.9	nM	CHEMBL1779987
9.02	IC50	0.955	nM	CHEMBL1780096
9.00	IC50	1	nM	CHEMBL5078680
9.00	IC50	1	nM	CHEMBL5088742
8.89	IC50	1.3	nM	CHEMBL2070735
8.89	IC50	1.3	nM	CHEMBL5723345
8.80	IC50	1.6	nM	CHEMBL2070732
8.71	IC50	1.96	nM	CHEMBL1780085
8.54	IC50	2.91	nM	CHEMBL1780116
8.49	IC50	3.2	nM	CHEMBL1779988
8.44	IC50	3.63	nM	CHEMBL2070914
8.41	IC50	3.86	nM	CHEMBL1780100
8.41	IC50	3.9	nM	CHEMBL1780089
8.38	IC50	4.2	nM	CHEMBL2070736
8.37	IC50	4.3	nM	CHEMBL1780097
8.36	IC50	4.36	nM	CHEMBL1780105
8.36	IC50	4.42	nM	CHEMBL1780111
8.30	IC50	5	nM	CHEMBL1779976
8.22	IC50	6	nM	CHEMBL1779984
8.22	IC50	6	nM	CHEMBL1779985
8.17	IC50	6.8	nM	CHEMBL2070604
8.17	IC50	6.79	nM	CHEMBL2070935
8.15	IC50	7	nM	CHEMBL1779990
8.14	IC50	7.3	nM	CHEMBL1780084
8.00	IC50	10	nM	CHEMBL2070595
7.92	IC50	12.1	nM	CHEMBL2070901
7.89	IC50	13	nM	CHEMBL1780087
7.88	IC50	13.1	nM	CHEMBL2070907
7.85	IC50	14	nM	CHEMBL2070592
7.85	IC50	14	nM	CHEMBL2070591
7.82	IC50	15	nM	CHEMBL1779986
7.81	IC50	15.5	nM	CHEMBL4128481
7.78	IC50	16.5	nM	CHEMBL1780086
7.77	IC50	17.1	nM	CHEMBL2070769
7.77	IC50	17.1	nM	CHEMBL2070912
7.77	IC50	17.1	nM	CHEMBL2070919
7.75	IC50	17.7	nM	CHEMBL2070932
7.72	IC50	19	nM	CHEMBL2070737
7.71	IC50	19.6	nM	CHEMBL1780102
7.67	IC50	21.6	nM	CHEMBL2070773
7.67	IC50	21.4	nM	CHEMBL2070933

PubChem BioAssay actives

143 with measured affinity, of 224 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
(3R,5S)-N-[(6-amino-2-pyridinyl)methyl]-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-5-phenylpiperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0001	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0002	uM
3-[[(2R)-4-(1,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl]-5-(trifluoromethyl)triazolo[4,5-d]pyrimidin-7-amine	1872585: Inhibition of PDE8B (unknown origin)	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]sulfamoyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0003	uM
5-cyclopropyl-3-[[(2R)-4-(1,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl]triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0009	uM
(3R,5S)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]-5-phenylpiperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0009	uM
(3S,5S)-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0010	uM
[(1S)-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl] 3-[[N-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxycarbonyl]anilino]methyl]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
[(1S)-1-[3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl]-2-(3,5-dichloro-1-oxidopyridin-1-ium-4-yl)ethyl] 3-[[2-[[(3R)-1-azabicyclo[2.2.2]octan-3-yl]oxy]-2-oxo-1-phenylethyl]amino]benzoate	1812119: Inhibition of PDE4 in human U-937 cells assessed as reduction in cAMP level by LANCE cAMP Assay	ic50	0.0010	uM
5-methyl-3-[[(2R)-4-(1,3-thiazol-2-ylmethyl)morpholin-2-yl]methyl]triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0013	uM
3-[[(2R)-4-(pyridin-2-ylmethyl)morpholin-2-yl]methyl]-5-(trifluoromethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0016	uM
(3R,5R)-5-(methoxymethyl)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-(oxan-4-ylmethyl)piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0020	uM
(3R,5R)-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[[(2R)-oxolan-2-yl]methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0029	uM
(3R,5R)-5-(methoxymethyl)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0032	uM
5-cyclopropyl-3-(3,4-dihydro-1H-isochromen-1-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0036	uM
(3S,5S)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0039	uM
(3R,5R)-5-(3-methyl-1,2,4-oxadiazol-5-yl)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0039	uM
3-[[(2R)-4-[(4-ethyl-1,3-thiazol-2-yl)methyl]morpholin-2-yl]methyl]-5-methyltriazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0042	uM
(3S,5S)-5-(methoxymethyl)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0043	uM
(3R,5R)-5-(methoxymethyl)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[[(2R)-oxolan-2-yl]methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0044	uM
(3R,5R)-N-[(6-amino-2-pyridinyl)methyl]-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0044	uM
2-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]-3,4-dihydro-1H-isoquinoline-4-carboxamide	598328: Inhibition of PDE8B	ic50	0.0050	uM
(3R,5R)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]-5-propylpiperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0060	uM
(3R,5R)-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0060	uM
3-[(3-tert-butyl-1H-pyrazol-5-yl)methyl]-5-cyclopropyltriazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0068	uM
5-cyclopropyl-3-[(3-cyclopropyl-1H-pyrazol-5-yl)methyl]triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0068	uM
[(3R,5R)-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-5-[(6-methyl-2-pyridinyl)methylcarbamoyl]piperidin-3-yl] acetate	598328: Inhibition of PDE8B	ic50	0.0070	uM
(3R,5R)-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-(oxan-4-ylmethyl)piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0073	uM
5-cyclopropyl-3-(oxan-2-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0100	uM
3-(oxan-2-ylmethyl)-5-(phenylsulfanylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0121	uM
(3R,5R)-5-(methoxymethyl)-1-[(5-methyl-2-pyrimidin-4-yl-1H-imidazol-4-yl)methyl]-N-(oxan-4-ylmethyl)piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0130	uM
5-(2-methyl-1,3-thiazol-4-yl)-3-(oxan-2-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0131	uM
3-(oxan-2-ylmethyl)-5-(trifluoromethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0140	uM
3-[[(2R)-oxolan-2-yl]methyl]-5-(trifluoromethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0140	uM
(3R,5R)-5-butyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[(6-methyl-2-pyridinyl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0150	uM
7,8-dimethoxy-N-[(2S)-1-(5-methyl-1H-pyrazol-3-yl)propan-2-yl]quinazolin-4-amine	1495738: Inhibition of full length recombinant human PDE8B using 3’,5’-[3H]cAMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0155	uM
(3R,5R)-N-[(6-amino-2-pyridinyl)methyl]-5-ethyl-1-[(5-methyl-2-morpholin-4-yl-1,3-oxazol-4-yl)methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0165	uM
5-[(3-fluorophenoxy)methyl]-3-(oxolan-2-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0171	uM
3-(oxan-2-ylmethyl)-5-thiophen-2-yltriazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0171	uM
5-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0171	uM
5-cyclopropyl-3-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0177	uM
3-[[(2R)-4-[(3,5-difluorophenyl)methyl]morpholin-2-yl]methyl]-5-methyltriazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0190	uM
(3R,5R)-5-ethyl-1-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methyl]-N-[[(2S)-oxolan-2-yl]methyl]piperidine-3-carboxamide	598328: Inhibition of PDE8B	ic50	0.0196	uM
tert-butyl 2-[(7-amino-5-cyclopropyltriazolo[4,5-d]pyrimidin-3-yl)methyl]piperidine-1-carboxylate	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0214	uM
5-ethyl-3-(oxan-2-ylmethyl)triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0216	uM
5-cyclopropyl-3-[[(2R)-4-(pyrimidin-2-ylmethyl)morpholin-2-yl]methyl]triazolo[4,5-d]pyrimidin-7-amine	677933: Inhibition of PDE8B expressed in Sf9 insect cells	ic50	0.0230	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Silicon Dioxide	decreases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
Aflatoxin B1	affects expression, decreases expression, increases methylation	3
Cyclic AMP	decreases reaction, increases metabolic processing, increases hydrolysis	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Dexamethasone	affects cotreatment, increases expression	2
Dipyridamole	decreases reaction, increases hydrolysis, increases metabolic processing	2
Nickel	decreases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
methyleugenol	decreases expression	1
bisphenol A	decreases methylation	1
9-(2-hydroxy-3-nonyl)adenine	decreases reaction, increases metabolic processing	1
sulforaphane	decreases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
trequinsin	decreases activity	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
E 4021	increases metabolic processing, decreases reaction	1
Roflumilast	decreases activity	1
L-826,141	decreases activity	1
abrine	decreases expression	1
jinfukang	decreases expression	1
Sildenafil Citrate	decreases reaction, increases metabolic processing	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, decreases expression	1
Endosulfan	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, increases expression	1

ChEMBL screening assays

35 unique, capped per target: 33 binding, 1 admet, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4479636	Binding	Inhibition of human PDE	Discovery of novel potent imidazo[1,2-b]pyridazine PDE10a inhibitors. — Bioorg Med Chem Lett
CHEMBL4680008	ADMET	Inhibition of PDE (unknown origin)	Fragment-Based Discovery of Novel Allosteric MEK1 Binders. — ACS Med Chem Lett
CHEMBL5723275	Functional	Affinity Biochemical interaction: (Enzymatic assay) EUB0002688aCl PDE8B	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety