PDE10A

Summary

PDE10A (phosphodiesterase 10A, HGNC:8772) is a protein-coding gene on chromosome 6q27, encoding cAMP and cAMP-inhibited cGMP 3’,5’-cyclic phosphodiesterase 10A (Q9Y233). Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides.

The protein encoded by this gene belongs to the cyclic nucleotide phosphodiesterase family. It plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. This protein can hydrolyze both cAMP and cGMP to the corresponding nucleoside 5’ monophosphate, but has higher affinity for cAMP, and is more efficient with cAMP as substrate. Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 10846 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dyskinesia, limb and orofacial, infantile-onset (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 44
• Clinical variants (ClinVar): 307 total — 4 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001385079

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8772
Approved symbol	PDE10A
Name	phosphodiesterase 10A
Location	6q27
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000112541
Ensembl biotype	protein_coding
OMIM	610652
Entrez	10846

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 19 protein_coding_CDS_not_defined, 10 protein_coding, 6 nonsense_mediated_decay, 5 retained_intron

ENST00000366882, ENST00000444465, ENST00000455853, ENST00000535229, ENST00000539869, ENST00000581850, ENST00000584179, ENST00000584911, ENST00000616273, ENST00000647590, ENST00000647768, ENST00000647837, ENST00000647989, ENST00000648884, ENST00000648917, ENST00000649247, ENST00000649273, ENST00000649362, ENST00000649754, ENST00000649761, ENST00000649882, ENST00000650248, ENST00000672224, ENST00000672859, ENST00000672902, ENST00000676766, ENST00000676767, ENST00000678161, ENST00000678462, ENST00000685292, ENST00000685414, ENST00000686660, ENST00000687318, ENST00000689721, ENST00000690845, ENST00000690869, ENST00000691218, ENST00000693427, ENST00000693476, ENST00000693627

RefSeq mRNA: 3 — MANE Select: NM_001385079 NM_001130690, NM_001385079, NM_006661

CCDS: CCDS94029

Canonical transcript exons

ENST00000539869 — 22 exons

Exon	Start	End
ENSE00000765997	165336123	165336211
ENSE00000765998	165339278	165339358
ENSE00000765999	165343391	165343502
ENSE00000766001	165379194	165379366
ENSE00000766002	165388298	165388453
ENSE00000766003	165392646	165392796
ENSE00000766004	165395181	165395264
ENSE00000766005	165396317	165396459
ENSE00000766006	165413501	165413687
ENSE00000766007	165416189	165416281
ENSE00000766008	165418635	165418777
ENSE00000766009	165428658	165428709
ENSE00000766011	165430287	165430345
ENSE00000766013	165431422	165431472
ENSE00000766015	165432974	165433129
ENSE00000766017	165435237	165435377
ENSE00000766019	165448928	165448977
ENSE00000828843	165450242	165450362
ENSE00001010817	165482315	165482343
ENSE00001152350	165543440	165543568
ENSE00003839079	165327289	165333127
ENSE00003839956	165661947	165663241

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 98.82.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8099 / max 375.3312, expressed in 895 samples.

FANTOM5 promoters (20 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76645	1.7634	312
76625	1.7181	303
76644	1.3154	265
76643	1.2902	210
76626	1.1804	621
76624	0.4837	29
76627	0.2664	144
76630	0.2016	78
76639	0.1546	64
76640	0.1321	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.82	gold quality
left uterine tube	UBERON:0001303	93.13	gold quality
cartilage tissue	UBERON:0002418	92.12	gold quality
left ovary	UBERON:0002119	91.12	gold quality
lateral globus pallidus	UBERON:0002476	90.63	gold quality
corpus epididymis	UBERON:0004359	89.48	gold quality
putamen	UBERON:0001874	88.59	gold quality
right ovary	UBERON:0002118	87.70	gold quality
adenohypophysis	UBERON:0002196	87.62	gold quality
stromal cell of endometrium	CL:0002255	86.73	gold quality
caudate nucleus	UBERON:0001873	86.63	gold quality
cortical plate	UBERON:0005343	86.31	gold quality
pituitary gland	UBERON:0000007	86.26	gold quality
ovary	UBERON:0000992	85.64	gold quality
right hemisphere of cerebellum	UBERON:0014890	84.00	gold quality
cerebellar cortex	UBERON:0002129	83.88	gold quality
cerebellar hemisphere	UBERON:0002245	83.84	gold quality
islet of Langerhans	UBERON:0000006	83.52	gold quality
nephron tubule	UBERON:0001231	83.07	gold quality
nucleus accumbens	UBERON:0001882	82.89	gold quality
cerebellum	UBERON:0002037	82.50	gold quality
tibia	UBERON:0000979	81.67	gold quality
heart right ventricle	UBERON:0002080	81.36	silver quality
ganglionic eminence	UBERON:0004023	80.77	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.42	gold quality
parietal pleura	UBERON:0002400	79.31	gold quality
right adrenal gland cortex	UBERON:0035827	79.16	gold quality
adrenal cortex	UBERON:0001235	79.06	gold quality
adrenal gland	UBERON:0002369	79.00	gold quality
renal glomerulus	UBERON:0000074	78.74	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	10076.64
E-CURD-119	yes	8883.68
E-HCAD-35	yes	4586.72
E-GEOD-137537	yes	1362.19
E-ANND-3	yes	7.65

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

283 targeting PDE10A, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-524-5P	99.98	73.43	4882

Literature-anchored findings (GeneRIF, showing 32)

• analysis of functional chimeras of the phosphodiesterase 5 and 10 tandem GAF domains (PMID:18635550)
• Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity. (PMID:19689430)
• The data of this results supported a model whereby PDE10A trafficking and localization can be regulated in response to local fluctuations in cAMP levels. (PMID:20610737)
• The present study is the first to demonstrate a central role of PDE10A in progressive pulmonary vascular remodeling. (PMID:21494592)
• HPRT-deficiency alters cAMP/PKA signaling pathway, which is in part due to the increased of PDE10A expression and activi (PMID:23691025)
• PDE10A activity in medium spiny neurons in Huntington’s disease might still be high in critical subcellular compartments, despite the overall striatal PDE10A decrease measured using positron-emission tomography. (PMID:24353339)
• Data provide evidence that PDE10 is involved in colon tumorigenesis and show its overexpression in colon tumor cells compared with colonocytes. (PMID:24704829)
• Lu AF33241 represents a novel PDE2A/PDE10A inhibitor tool which can penetrate the blood brain barrier. (PMID:25941078)
• cGMP PDE isozymes, PDE5 and 10, are elevated in colon tumor cells compared with normal colonocytes, and inhibitors and siRNAs can selectively suppress colon tumor cell growth (PMID:26299804)
• Longitudinal data in a cohort of patients with early Huntington disease found PDE10 to be a useful biomarker of disease progression. (PMID:26802091)
• The PDE10A gene is currently known to be comprised of 23 exons26 and maps to chromosome 6q26,17, 18 a region previously associated with bipolar disorder. (PMID:26905414)
• germline PDE10A mutations associated with hyperkinetic movement disorder (PMID:27058446)
• We have demonstrated that de novo dominant mutations in PDE10A are the cause of a unique movement disorder characterized by benign childhood-onset chorea and typical MRI abnormalities of the striatum. (PMID:27058447)
• Collectively, these findings highlight a novel thermoregulatory role for PDE10A in mouse and human adipocytes and promote PDE10A inhibitors as promising candidates for the treatment of obesity and diabetes. (PMID:27247380)
• The method proposed for quantification of [(11)C]Lu AE92686 binding in applied studies in NHP is based on 63 min PET data and SRTM with cerebellum as a reference region. The study supports that [(11)C]Lu AE92686 can be used for PET examinations of PDE10A binding also in substantia nigra. (PMID:27817159)
• Studied what regions of the PDE10A gene are transcribed in human putamen and caudate nucleus brain tissue, two sub-regions of the striatum. Surprisingly, twelve novel transcripts were detected, of which three were predicted to be translated into PDE10A proteins with unique N-termini.studies show that there is much more transcript diversity within the PDE10A gene region than initially believed. (PMID:28042091)
• Results indicate that aging is associated with a considerable physiological reduction of the availability of phosphodiesterase 10A enzyme enzyme in the striatum. (PMID:28254508)
• 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)
• childhood onset of chorea with normal cognition and striatal hyperintensities should prompt further evaluation beyond benign hereditary chorea and heterozygous or homozygous mutations in PDE10A can cause such a phenotype. More number of cases needs to be identified before a definite phenotype genotype correlation can be made in such cases. (PMID:29130591)
• This report that PDE10A mutation is associated with familial Benign hereditary chorea. (PMID:29165877)
• natural selection on genetic variants in the PDE10A gene have increased spleen size in the Bajau population of Indonesia, providing them with a larger reservoir of oxygenated red blood cells (PMID:29677510)
• indicate an association between PDE10A and ADCY5 mutations and pre/postsynaptic molecular changes, substantia nigra damage, and white and gray matter changes within the striatocortical pathways (PMID:30345538)
• PDE10A IgG defines a novel rare neurologic autoimmune syndrome and expands the spectrum of diagnosable paraneoplastic CNS disorders. (PMID:31315972)
• Mutations in the regulatory GAF domains of PDE10A that cause hyperkinetic syndromes in humans lead to misprocessing of the PDE10A enzyme that ultimately leads to targeted degradation by the ubiquitin proteasome system or clearance by autophagy. Both mechanisms result in a paucity of PDE10A activity that lead to a loss of movement coordination. (PMID:31871190)
• Phosphodiesterases PDE2A and PDE10A both change mRNA expression in the human brain with age, but only PDE2A changes in a region-specific manner with psychiatric disease. (PMID:32119913)
• LINC00473 downregulation facilitates trophoblast cell migration and invasion via the miR-15a-5p/LITAF axis in pre-eclampsia. (PMID:33908139)
• Papaverine, a Phosphodiesterase 10A Inhibitor, Ameliorates Quinolinic Acid-Induced Synaptotoxicity in Human Cortical Neurons. (PMID:33914237)
• Role of PDE10A in vascular smooth muscle cell hyperplasia and pathological vascular remodelling. (PMID:34550322)
• Phosphodiesterase 10A (PDE10A) as a novel target to suppress beta-catenin and RAS signaling in epithelial ovarian cancer. (PMID:36324187)
• Expanding the genotype-phenotype landscape of PDE10A-associated movement disorders. (PMID:36805523)
• PDE10A Mutation as an Emerging Cause of Childhood-Onset Hyperkinetic Movement Disorders: A Review of All Published Cases. (PMID:38442915)
• Alterations of striatal phosphodiesterase 10 A and their association with recurrence rate in bipolar I disorder. (PMID:39358334)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pde10a	ENSDARG00000003449
mus_musculus	Pde10a	ENSMUSG00000023868
rattus_norvegicus	Pde10a	ENSRNOG00000011310
caenorhabditis_elegans	pde-5	WBGENE00016328

Paralogs (20): PDE4A (ENSG00000065989), PDE8A (ENSG00000073417), PDE6C (ENSG00000095464), PDE4C (ENSG00000105650), PDE8B (ENSG00000113231), 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

cAMP and cAMP-inhibited cGMP 3’,5’-cyclic phosphodiesterase 10A — Q9Y233 (reviewed: Q9Y233)

All UniProt accessions (16): Q9Y233, A0A087WUD0, A0A1B1UZQ1, A0A3B3IRL3, A0A3B3IRU7, A0A3B3IS50, A0A3B3ISJ6, A0A3B3IT18, A0A3B3ITT8, A0A5F9ZHF9, A0A5F9ZI67, A0A7I2V301, A0A7I2V618, A0A7I2YQI4, A0A7I2YQV2, A0AAA9X175

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate. May play a critical role in regulating cAMP and cGMP levels in the striatum, a region of the brain that contributes to the control of movement and cognition.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Abundant in the putamen and caudate nucleus regions of brain and testis, moderately expressed in the thyroid gland, pituitary gland, thalamus and cerebellum.

Post-translational modifications. Phosphorylated on Thr-16.

Disease relevance. Dyskinesia, limb and orofacial, infantile-onset (IOLOD) [MIM:616921] An autosomal recessive, early-onset hyperkinetic movement disorder characterized by axial hypotonia, dyskinesia of the limbs and trunk, orofacial dyskinesia, drooling, and dysarthria. The severity of the hyperkinesis is variable. The disease is caused by variants affecting the gene represented in this entry. Striatal degeneration, autosomal dominant 2 (ADSD2) [MIM:616922] An autosomal dominant disorder characterized by striatal degeneration and dysfunction of basal ganglia, resulting in hyperkinesis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by dipyridamole and moderately by IBMX. cGMP acts as an allosteric activator.

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. The tandem GAF domains bind cAMP, and regulate enzyme activity. The binding of cAMP stimulates enzyme activity. Composed of a C-terminal catalytic domain containing two divalent metal sites and an N-terminal regulatory domain which contains one cyclic nucleotide-binding region.

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

Miscellaneous. Produced by alternative initiation. Based on proteomic data.

Similarity. Belongs to the cyclic nucleotide phosphodiesterase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9Y233-3	3	yes
Q9Y233-1	PDE10A1
Q9Y233-2	PDE10A2

RefSeq proteins (3): NP_001124162, NP_001372008, NP_006652 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002073	PDEase_catalytic_dom	Domain
IPR003018	GAF	Domain
IPR003607	HD/PDEase_dom	Domain
IPR023088	PDEase	Family
IPR023174	PDEase_CS	Conserved_site
IPR029016	GAF-like_dom_sf	Homologous_superfamily
IPR036971	PDEase_catalytic_dom_sf	Homologous_superfamily

Pfam: PF00233, PF01590

Enzyme classification (BRENDA):

• EC 3.1.4.17 — 3’,5’-cyclic-nucleotide phosphodiesterase (BRENDA: 27 organisms, 83 substrates, 296 inhibitors, 106 Km, 31 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3’,5’-CAMP	0.0001–7	41
3’,5’-CGMP	—	23
CAMP	0.0002–1.6	15
CGMP	0.0002–1	12
2’,3’-CAMP	0.0038–0.0052	2
5’-AMP	0.0014–0.0016	2
5’-ATP	0.0033–0.0125	2
5’-PAPA	0.204	1
5’-PAPG	0.355	1
ADENOSINE 3’,5’-CYCLIC PHOSPHATE	0.012	1
GUANOSINE 3’,5’-CYCLIC PHOSPHATE	0.025	1

Catalyzed reactions (Rhea), 3 shown:

• a nucleoside 3’,5’-cyclic phosphate + H2O = a nucleoside 5’-phosphate + H(+) (RHEA:14653)
• 3’,5’-cyclic GMP + H2O = GMP + H(+) (RHEA:16957)
• 3’,5’-cyclic AMP + H2O = AMP + H(+) (RHEA:25277)

UniProt features (83 total): helix 29, binding site 13, strand 11, sequence variant 7, turn 5, compositionally biased region 4, domain 3, region of interest 3, splice variant 2, mutagenesis site 2, chain 1, active site 1, modified residue 1, sequence conflict 1

Structure

Experimental structures (PDB)

359 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
2OUR	X-RAY DIFFRACTION	1.45
2OUS	X-RAY DIFFRACTION	1.45
4LM4	X-RAY DIFFRACTION	1.48
4LM3	X-RAY DIFFRACTION	1.49
2OUU	X-RAY DIFFRACTION	1.52
4LLK	X-RAY DIFFRACTION	1.55
4LM2	X-RAY DIFFRACTION	1.55
2OUN	X-RAY DIFFRACTION	1.56
2OUP	X-RAY DIFFRACTION	1.56
2OUV	X-RAY DIFFRACTION	1.56
4LLJ	X-RAY DIFFRACTION	1.56
5C28	X-RAY DIFFRACTION	1.56
4MRZ	X-RAY DIFFRACTION	1.58
4LM1	X-RAY DIFFRACTION	1.6
4LKQ	X-RAY DIFFRACTION	1.62
4MSA	X-RAY DIFFRACTION	1.62
4LM0	X-RAY DIFFRACTION	1.66
5C1W	X-RAY DIFFRACTION	1.7
7QPF	X-RAY DIFFRACTION	1.7
4LLP	X-RAY DIFFRACTION	1.75
4LLX	X-RAY DIFFRACTION	1.75
5SI1	X-RAY DIFFRACTION	1.75
5SIM	X-RAY DIFFRACTION	1.75
5AXQ	X-RAY DIFFRACTION	1.77
4MS0	X-RAY DIFFRACTION	1.79
3SN7	X-RAY DIFFRACTION	1.82
5SIS	X-RAY DIFFRACTION	1.85
5SFE	X-RAY DIFFRACTION	1.86
5UWF	X-RAY DIFFRACTION	1.87
2OUQ	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y233-F1	71.05	0.36

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): 791 (proton donor)

Ligand- & substrate-binding residues (13): 562–563; 606–607; 640; 659; 791; 791; 795; 829; 830; 830; 940; 992 …

Post-translational modifications (1): 282

Mutagenesis-validated functional residues (2):

Position	Phenotype
830	loss of activity and of zinc binding.
830	reduces activity 1000-fold.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-418457	cGMP effects
R-HSA-418555	G alpha (s) signalling events

MSigDB gene sets: 297 (showing top): RNGTGGGC_UNKNOWN, BENPORATH_ES_WITH_H3K27ME3, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_CYCLIC_NUCLEOTIDE_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_CYCLIC_NUCLEOTIDE_CATABOLIC_PROCESS, MORF_RAD51L3, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PAX2_01, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, WATANABE_COLON_CANCER_MSI_VS_MSS_UP

GO Biological Process (7): cAMP catabolic process (GO:0006198), signal transduction (GO:0007165), negative regulation of receptor guanylyl cyclase signaling pathway (GO:0010754), cGMP catabolic process (GO:0046069), regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0106070), negative regulation of cAMP/PKA signal transduction (GO:0141162), regulation of cAMP/PKA signal transduction (GO:0141161)

GO Molecular Function (13): 3’,5’-cyclic-nucleotide phosphodiesterase activity (GO:0004114), 3’,5’-cyclic-AMP phosphodiesterase activity (GO:0004115), 3’,5’-cGMP-stimulated cyclic-nucleotide phosphodiesterase activity (GO:0004118), cAMP binding (GO:0030552), cGMP binding (GO:0030553), metal ion binding (GO:0046872), 3’,5’-cyclic-GMP phosphodiesterase activity (GO:0047555), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), cyclic-nucleotide phosphodiesterase activity (GO:0004112), protein binding (GO:0005515), phosphoric diester hydrolase activity (GO:0008081), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytosol (GO:0005829), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Nitric oxide stimulates guanylate cyclase	1
GPCR downstream signalling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
3’,5’-cyclic-nucleotide phosphodiesterase activity	3
purine ribonucleotide catabolic process	2
cyclic nucleotide catabolic process	2
cAMP/PKA signal transduction	2
cyclic nucleotide binding	2
anion binding	2
cellular anatomical structure	2
cAMP metabolic process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor guanylyl cyclase signaling pathway	1
negative regulation of signal transduction	1
cGMP metabolic process	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
regulation of G protein-coupled receptor signaling pathway	1
regulation of cAMP/PKA signal transduction	1
negative regulation of intracellular signal transduction	1
regulation of intracellular signal transduction	1
cyclic-nucleotide phosphodiesterase activity	1
adenyl ribonucleotide binding	1
guanyl ribonucleotide binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
phosphoric diester hydrolase activity	1
binding	1
phosphoric ester hydrolase activity	1
catalytic activity	1
cytoplasm	1
synapse	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1304 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PDE10A	ALDH7A1	P49419	893
PDE10A	PPP1R1B	Q9UD71	577
PDE10A	PDE4A	P27815	575
PDE10A	ADCY5	O95622	571
PDE10A	PDE7A	Q13946	543
PDE10A	ADORA2A	P29274	509
PDE10A	DRD2	P14416	497
PDE10A	KLHL11	Q9NVR0	492
PDE10A	GPR88	Q9GZN0	479
PDE10A	GNG7	O60262	454
PDE10A	HTT	P42858	444
PDE10A	DRD1	P21728	443
PDE10A	ARPP21	Q9UBL0	441
PDE10A	N4BP2	Q86UW6	439
PDE10A	MBIP	Q9NS73	433

IntAct

2 interactions, top by confidence:

A	B	Type	Score
CSN1S1	TIMP3	psi-mi:“MI:0914”(association)	0.350
WDR3	PDE10A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): PDE10A (Affinity Capture-MS), PDE10A (Affinity Capture-RNA), PDE10A (Synthetic Lethality), PDE10A (Affinity Capture-MS), RPS12 (Cross-Linking-MS (XL-MS)), PDE10A (Cross-Linking-MS (XL-MS)), RPS12 (Cross-Linking-MS (XL-MS)), PDE10A (Affinity Capture-MS), RNF220 (Affinity Capture-MS), RNF220 (Affinity Capture-Western), PDE10A (Affinity Capture-Western), PDE10A (Protein-peptide)

ESM2 similar proteins: A6QLK5, A6ZKI3, D2HBJ8, O15519, O94955, O95751, P0CW24, P10272, Q0V9G5, Q17QF6, Q17RB0, Q1JQ94, Q2TBA3, Q5RD56, Q5RER6, Q5XGZ2, Q63053, Q6NTR6, Q6P5G6, Q6SEH4, Q6SEH5, Q70Z35, Q7JV70, Q7K1U0, Q7LC44, Q7TPY9, Q86TG7, Q8AWC3, Q8C1C8, Q8CA95, Q8N165, Q8N635, Q8ND90, Q8QZR7, Q8TCU6, Q8VHZ4, Q8WNV3, Q96PV4, Q9BWD3, Q9BYG7

Diamond homologs: B3LVW5, B3P3K2, B4G4E5, B4HEM4, B4JXX2, B4K9L4, B4LVU6, B4NAL6, B4PSS5, B4QZU1, B7YZV4, H2QL32, O00408, O54735, O70628, O76074, O76083, O77746, O89084, P0C1Q2, P11541, P14099, P14100, P14644, P14646, P16499, P16586, P23439, P23440, P27664, P27815, P30645, P33726, P35913, P51160, P52731, P54748, P54750, P91119, Q01061

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKACA	unknown	PDE10A	phosphorylation
PF-2545920	down-regulates	PDE10A	“chemical inhibition”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	135
Likely benign	111
Benign	21

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
225634	NM_001385079.1(PDE10A):c.1144G>C (p.Ala382Pro)	Pathogenic
225635	NM_001385079.1(PDE10A):c.1798T>C (p.Phe600Leu)	Pathogenic
225636	NM_001385079.1(PDE10A):c.1696T>C (p.Phe566Leu)	Pathogenic
871037	NM_001385079.1(PDE10A):c.2575C>T (p.Gln859Ter)	Pathogenic
1708178	NM_001385079.1(PDE10A):c.2795T>G (p.Ile932Ser)	Likely pathogenic
1708179	NM_001385079.1(PDE10A):c.2133_2142del (p.Ser712fs)	Likely pathogenic
2031793	NM_001385079.1(PDE10A):c.1698C>G (p.Phe566Leu)	Likely pathogenic
3780106	NM_001385079.1(PDE10A):c.2375dup (p.Asn792fs)	Likely pathogenic
807460	NM_001385079.1(PDE10A):c.1450C>T (p.Arg484Trp)	Likely pathogenic

SpliceAI

5208 predictions. Top by Δscore:

Variant	Effect	Δscore
6:165336218:CCA:C	acceptor_gain	1.0000
6:165336219:CA:C	acceptor_gain	1.0000
6:165336220:A:C	acceptor_gain	1.0000
6:165336230:C:CT	acceptor_gain	1.0000
6:165336230:C:T	acceptor_gain	1.0000
6:165339272:TCATA:T	donor_loss	1.0000
6:165339273:CATA:C	donor_loss	1.0000
6:165339274:ATAC:A	donor_loss	1.0000
6:165339275:TA:T	donor_loss	1.0000
6:165339276:ACCTG:A	donor_loss	1.0000
6:165339277:C:CT	donor_loss	1.0000
6:165339357:CC:C	acceptor_gain	1.0000
6:165339358:CC:C	acceptor_gain	1.0000
6:165379252:T:TA	donor_gain	1.0000
6:165379367:C:CC	acceptor_gain	1.0000
6:165388293:CTCA:C	donor_loss	1.0000
6:165388294:TCA:T	donor_loss	1.0000
6:165388295:CACCT:C	donor_loss	1.0000
6:165388296:A:AC	donor_gain	1.0000
6:165388296:ACC:A	donor_loss	1.0000
6:165388297:C:CC	donor_gain	1.0000
6:165388456:T:C	acceptor_gain	1.0000
6:165388456:T:TC	acceptor_gain	1.0000
6:165392642:CCAC:C	donor_loss	1.0000
6:165392643:CACCT:C	donor_loss	1.0000
6:165392644:ACC:A	donor_loss	1.0000
6:165392645:C:CA	donor_loss	1.0000
6:165392792:CAAAG:C	acceptor_gain	1.0000
6:165392795:AG:A	acceptor_gain	1.0000
6:165392796:GC:G	acceptor_loss	1.0000

AlphaMissense

6871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:165333109:C:A	W752C	1.000
6:165333109:C:G	W752C	1.000
6:165333111:A:G	W752R	1.000
6:165333111:A:T	W752R	1.000
6:165336168:A:G	L731P	1.000
6:165336179:G:C	C727W	1.000
6:165336180:C:T	C727Y	1.000
6:165336181:A:G	C727R	1.000
6:165336189:G:T	A724D	1.000
6:165336203:G:C	F719L	1.000
6:165336203:G:T	F719L	1.000
6:165336204:A:C	F719C	1.000
6:165336204:A:G	F719S	1.000
6:165336205:A:G	F719L	1.000
6:165339308:T:A	R706S	1.000
6:165339308:T:G	R706S	1.000
6:165339357:C:A	G690V	1.000
6:165339357:C:T	G690D	1.000
6:165339358:C:A	G690C	1.000
6:165339358:C:G	G690R	1.000
6:165339358:C:T	G690S	1.000
6:165343400:G:C	F686L	1.000
6:165343400:G:T	F686L	1.000
6:165343401:A:G	F686S	1.000
6:165343402:A:C	F686V	1.000
6:165343402:A:G	F686L	1.000
6:165343413:A:T	I682K	1.000
6:165343442:C:A	W672C	1.000
6:165343442:C:G	W672C	1.000
6:165343444:A:G	W672R	1.000

dbSNP variants (sampled 300 via entrez): RS1000002899 (6:165408937 G>A,T), RS1000006271 (6:165397391 G>T), RS1000010514 (6:165620157 T>A), RS1000013555 (6:165916885 C>G), RS1000016359 (6:165642860 A>C), RS1000019106 (6:165607720 T>A,C), RS1000027224 (6:165796785 A>T), RS1000027446 (6:165833799 G>T), RS1000029650 (6:165341595 C>A,T), RS1000033047 (6:165880680 G>C), RS1000041385 (6:165335822 C>T), RS1000043026 (6:165394093 GT>G), RS1000049545 (6:165874492 G>T), RS1000053968 (6:165715907 C>G,T), RS1000056970 (6:165805150 G>A,T)

Disease associations

OMIM: gene MIM:610652 | disease phenotypes: MIM:616922, MIM:616921

GenCC curated gene-disease

Disease	Classification	Inheritance
dyskinesia, limb and orofacial, infantile-onset	Strong	Autosomal recessive
striatal degeneration, autosomal dominant 2	Strong	Autosomal dominant
infantile-onset generalized dyskinesia with orofacial involvement	Strong	Autosomal recessive
childhood-onset benign chorea with striatal involvement	Supportive	Autosomal dominant

Mondo (5): striatal degeneration, autosomal dominant 2 (MONDO:0014835), infantile-onset generalized dyskinesia with orofacial involvement (MONDO:0044637), intellectual disability (MONDO:0001071), (MONDO:0014834), childhood-onset benign chorea with striatal involvement (MONDO:0044332)

Orphanet (2): Infantile-onset generalized dyskinesia with orofacial involvement (Orphanet:494526), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000726	Dementia
HP:0000739	Anxiety
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0001268	Mental deterioration
HP:0001270	Motor delay
HP:0001300	Parkinsonism
HP:0001337	Tremor
HP:0002072	Chorea
HP:0002194	Delayed gross motor development
HP:0002307	Drooling
HP:0002310	Orofacial dyskinesia
HP:0002317	Unsteady gait
HP:0002359	Frequent falls
HP:0002487	Hyperkinetic movements
HP:0002548	Parkinsonism with favorable response to dopaminergic medication
HP:0003593	Infantile onset
HP:0003680	Nonprogressive
HP:0008936	Axial hypotonia
HP:0010994	Abnormal corpus striatum morphology
HP:0011470	Nasogastric tube feeding in infancy
HP:0011968	Feeding difficulties
HP:0012444	Brain atrophy
HP:0031206	Striatal T2 hyperintensity
HP:0100248	Hemiballismus
HP:0100660	Dyskinesia

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST000713_9	Conduct disorder (symptom count)	1.000000e-06
GCST001856_1	Thyroid hormone levels	1.000000e-24
GCST001856_20	Thyroid hormone levels	5.000000e-09
GCST001856_24	Thyroid hormone levels	6.000000e-20
GCST002498_13	Age-related nuclear cataracts	9.000000e-06
GCST003059_12	Parkinson’s disease	1.000000e-06
GCST003455_37	Spherical equivalent (joint analysis main effects and education interaction)	9.000000e-09
GCST003988_14	Hypothyroidism	9.000000e-12
GCST004276_1	Plasma thyroid-stimulating hormone levels	5.000000e-16
GCST004276_7	Plasma thyroid-stimulating hormone levels	6.000000e-10
GCST004280_81	Diastolic blood pressure	2.000000e-09
GCST004780_9	Cortisol levels (saliva)	8.000000e-06
GCST005246_2	Inhibitory control	5.000000e-06
GCST006166_23	Diastolic blood pressure x alcohol consumption interaction (2df test)	6.000000e-11
GCST006897_6	Hyperthyroidism	5.000000e-10
GCST006898_5	Hypothyroidism	2.000000e-08
GCST007094_129	Diastolic blood pressure	5.000000e-12
GCST007099_49	Systolic blood pressure	2.000000e-07
GCST007576_203	Chronotype	7.000000e-11
GCST007932_20	Medication use (thyroid preparations)	2.000000e-10
GCST008158_93	Body mass index	4.000000e-06
GCST008163_560	Height	2.000000e-06
GCST008165_9	Thyroid stimulating hormone levels	5.000000e-26
GCST008362_112	Birth weight	3.000000e-07
GCST008362_164	Birth weight	2.000000e-13
GCST008367_15	Plasma anti-thyroglobulin and anti-thyroid peroxidase levels (bivariate analysis)	3.000000e-06
GCST008367_19	Plasma anti-thyroglobulin and anti-thyroid peroxidase levels (bivariate analysis)	3.000000e-06
GCST009391_1319	Metabolite levels	6.000000e-06
GCST009391_1404	Metabolite levels	4.000000e-06
GCST009391_167	Metabolite levels	1.000000e-06

EFO canonical traits (24, from GWAS)

EFO ID	Trait name
EFO:0004730	hormone measurement
EFO:0004784	self reported educational attainment
EFO:0006336	diastolic blood pressure
EFO:0005843	cortisol measurement
EFO:0008467	behavioural inhibitory control measurement
EFO:0004329	alcohol drinking
EFO:0006335	systolic blood pressure
EFO:0008328	chronotype measurement
EFO:0009933	Thyroid preparation use measurement
EFO:0004340	body mass index
EFO:0004344	birth weight
EFO:0010519	pantothenic acid measurement
EFO:0005132	5-HIAA measurement
EFO:0009768	glutamine measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density
EFO:0004980	appendicular lean mass
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363066 (PROTEIN FAMILY), CHEMBL4409 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 162,809 (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
CHEMBL1520	VARDENAFIL	4	21,078
CHEMBL192	SILDENAFIL	4	41,819
CHEMBL348000	CINCHOPHEN	4	3,180
CHEMBL932	DIPYRIDAMOLE	4	51,743
CHEMBL19224	PAPAVERINE	3	22,172
CHEMBL219376	OXYCINCHOPHEN	2	513
CHEMBL28079	ZAPRINAST	2	16,158
CHEMBL4549658	PF-06835919	2	19
CHEMBL5314924	MK-8189	2	14
CHEMBL562318	MARDEPODECT	2	432
CHEMBL98123	PAPAVERINE HYDROCHLORIDE	2	4,085
CHEMBL2001019	PF-04217903	1	1,286
CHEMBL2180408	JNJ-42396302	1	12
CHEMBL3770459	LENRISPODUN PHOSPHATE	1	14
CHEMBL3942498	PBF-999	1	85
CHEMBL4297354	AZD-7687	1	199

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 (9 total), top 9:

Ligand	Action	Affinity	Parameter
MK-8189	Inhibition	10.54	pKi
TP-10	Inhibition	9.52	pIC50
mardepodect	Inhibition	9.43	pIC50
compound 19 [PMID: 22142545]	Inhibition	9.0	pKi
compound 27 [PMID: 22142545]	Inhibition	8.3	pKi
PBF-999	Inhibition	8.24	pIC50
TC-E 5005	Inhibition	8.14	pIC50
papaverine	Inhibition	7.68	pIC50
PDE4 inhibitor 16	Inhibition	6.04	pIC50

Binding affinities (BindingDB)

4241 measured of 4748 human assays (4748 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[[(1R,2R)-2-quinolin-2-ylcyclopropyl]methoxy]pyrimidin-4-amine	KI	0.0006 nM	US-8785467: Alkoxy pyrimidine PDE10 inhibitors
2-[3-[3-(2,6-dimethoxy-3-pyridinyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.001 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(6,6-dimethyl-2,5-dihydropyran-4-yl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.001 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)methylamino]-6-[[(1S,2S)-2-quinolin-2-ylcyclopropyl]methoxy]pyridazin-3-one	KI	0.001 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
6-[[(1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl]methoxy]-4-[(2,5-dimethylpyrazol-3-yl)methylamino]-2-methylpyridazin-3-one	KI	0.001 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
2-(3-(3-(2,2-dimethyl-3,6- dihydro-2H-pyran-4-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline and 2-(3-(3-(6,6-dimethyl-3,6- dihydro-2H-pyran-4-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline	IC50	0.001 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(6-methoxy-2-pyridinyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.001 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.0011 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(2-methoxy-3-pyridinyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.002 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(4-chloro-3-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.002 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
US8957073, 4.23	IC50	0.002 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[(1S,2S)-2-[[2-methyl-5-(1,3,5-trimethylpyrazol-4-yl)pyrimidin-4-yl]oxymethyl]cyclopropyl]quinoline	KI	0.002 nM	US-8975261: Aryloxmethyl cyclopropane derivatives as PDE10 inhibitors
2-[(E)-2-[6-[5-[(3,4-dimethoxyphenyl)methyl]-3-methyl-1,2,4-triazol-1-yl]-2-methylpyrimidin-4-yl]ethenyl]quinoline	KI	0.002 nM	US-9200001: Triazolyl PDE10 inhibitors
4-[5-[(3,4-dimethoxyphenyl)methyl]-3-methyl-1,2,4-triazol-1-yl]-2-methyl-6-[(E)-2-pyridin-2-ylethenyl]pyrimidine	KI	0.002 nM	US-9200001: Triazolyl PDE10 inhibitors
6-[[(1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl]methoxy]-4-[(2,6-dimethyl-3-pyridinyl)methylamino]-2-methylpyridazin-3-one	KI	0.002 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
6-[[(1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl]methoxy]-2-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)methylamino]pyridazin-3-one	KI	0.002 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
6-[[(1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl]methoxy]-2-methyl-4-[(5-methyl-1,3-thiazol-2-yl)methylamino]pyridazin-3-one	KI	0.002 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
4-[(2,5-dimethylpyrazol-3-yl)methylamino]-6-[[(1S,2S)-2-(5-methoxy-2-pyridinyl)cyclopropyl]methoxy]-2-methylpyridazin-3-one	KI	0.002 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
2-[3-[3-(4-methylsulfonylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.00262 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(6-methyl-3-pyridinyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.00279 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
5-[3-(1-quinolin-2-ylazetidin-3-yl)pyrazin-2-yl]pyridin-2-amine	IC50	0.00278 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[2-[6-[5-[(3,4-dimethoxyphenyl)methyl]-3-methyl-1,2,4-triazol-1-yl]-2-methylpyrimidin-4-yl]cyclopropyl]-1-methylbenzimidazole	KI	0.003 nM	US-9200001: Triazolyl PDE10 inhibitors
4-[(2,5-dimethylpyrazol-3-yl)methylamino]-2-methyl-6-[[(1S,2S)-2-(5-methyl-2-pyridinyl)cyclopropyl]methoxy]pyridazin-3-one	KI	0.003 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
4-[(2,6-dimethyl-3-pyridinyl)methylamino]-6-[[(1S,2S)-2-(5-methoxy-2-pyridinyl)cyclopropyl]methoxy]-2-methylpyridazin-3-one	KI	0.003 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
6-chloro-N-[(2,5-dimethylpyrazol-3-yl)methyl]-5-methyl-2-[[(1S,2S)-2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy]pyrimidin-4-amine	KI	0.0032 nM	US-8785467: Alkoxy pyrimidine PDE10 inhibitors
2-[3-[3-(4-methoxy-3-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.0035 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
5-[3-(1-quinolin-2-ylazetidin-3-yl)pyrazin-2-yl]pyridin-3-amine	IC50	0.00376 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(6-fluoro-3-pyridinyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.004 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(3-fluoro-4-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.004 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(3-chloro-4-fluorophenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.004 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[2-[6-[5-[(3,4-dimethoxyphenyl)methyl]-3-methyl-1,2,4-triazol-1-yl]-2-methylpyrimidin-4-yl]ethyl]quinoline	KI	0.004 nM	US-9200001: Triazolyl PDE10 inhibitors
3-methoxy-1-methyl-5-[2-methyl-4-[[(1S,2S)-2-quinolin-2-ylcyclopropyl]methoxy]pyrimidin-5-yl]pyridin-2-one	KI	0.004 nM	US-9273033: Substituted pyridone derivatives as PDE10 inhibitors
4-[(2,6-dimethyl-3-pyridinyl)methylamino]-2-methyl-6-[[(1S,2S)-2-quinolin-2-ylcyclopropyl]methoxy]pyridazin-3-one	KI	0.004 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
6-[[(1S,2S)-2-(5-methoxy-2-pyridinyl)cyclopropyl]methoxy]-2-methyl-4-[(5-methyl-1,3-thiazol-2-yl)methylamino]pyridazin-3-one	KI	0.004 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
5-bromo-6-[[(1S,2S)-2-(5-methoxy-2-pyridinyl)cyclopropyl]methoxy]-2-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)methylamino]pyridazin-3-one	KI	0.004 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
5-chloro-6-[[(1S,2S)-2-(5-methoxy-2-pyridinyl)cyclopropyl]methoxy]-2-methyl-4-[(5-methyl-1,3,4-thiadiazol-2-yl)methylamino]pyridazin-3-one	KI	0.004 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
2-[3-[3-(3-fluoro-5-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.005 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(3,4-dimethylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.005 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[2-[6-[5-[(3,4-dimethoxyphenyl)methyl]-3-methyl-1,2,4-triazol-1-yl]-2-methylpyrimidin-4-yl]cyclopropyl]-1H-benzimidazole	KI	0.005 nM	US-9200001: Triazolyl PDE10 inhibitors
2-[(1R,2R)-2-[6-[5-[(3,4-dimethoxyphenyl)methyl]-3-methyl-1,2,4-triazol-1-yl]-2-methylpyrimidin-4-yl]cyclopropyl]-1H-benzimidazole	KI	0.005 nM	US-9200001: Triazolyl PDE10 inhibitors
4-[(2,5-dimethylpyrazol-3-yl)methylamino]-2-methyl-6-[[(1S,2S)-2-(6-methyl-2-pyridinyl)cyclopropyl]methoxy]pyridazin-3-one	KI	0.005 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
6-[[(1S,2S)-2-(6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopropyl]methoxy]-2-methyl-4-[(1-methylpyrazol-4-yl)methylamino]pyridazin-3-one	KI	0.005 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors
2-[3-[3-(2-methyl-3-pyridinyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.006 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(4-ethoxy-3-fluorophenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.006 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(4-fluoro-3-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.006 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
1,6-dimethyl-5-[2-methyl-4-[[(1S,2S)-2-quinolin-2-ylcyclopropyl]methoxy]pyrimidin-5-yl]pyridin-2-one	KI	0.006 nM	US-9273033: Substituted pyridone derivatives as PDE10 inhibitors
2-[3-[3-(3-chloro-4-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.0067 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(3-chloro-5-methylphenyl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.007 nM	US-9718803: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-[3-[3-(1H-pyrazol-4-yl)pyrazin-2-yl]azetidin-1-yl]quinoline	IC50	0.007 nM	US-8957073: Unsaturated nitrogen heterocyclic compounds useful as PDE10 inhibitors
2-methyl-6-[[(1S,2S)-2-(5-methyl-2-pyridinyl)cyclopropyl]methoxy]-4-[(5-methyl-1,3-thiazol-2-yl)methylamino]pyridazin-3-one	KI	0.007 nM	US-9353104: Substituted pyridizinone derivatives as PDE10 inhibitors

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	CHEMBL3746993
11.00	Ki	0.01	nM	CHEMBL3745790
11.00	Ki	0.01	nM	CHEMBL3746277
11.00	Ki	0.01	nM	CHEMBL3960405
11.00	Ki	0.01	nM	CHEMBL4111794
11.00	IC50	0.01	nM	CHEMBL3686937
11.00	Ki	0.01	nM	CHEMBL5874748
11.00	Ki	0.01	nM	CHEMBL5795042
11.00	Ki	0.01	nM	CHEMBL5976716
11.00	Ki	0.01	nM	CHEMBL5996071
11.00	Ki	0.01	nM	CHEMBL5897423
11.00	Ki	0.01	nM	CHEMBL5856126
10.97	IC50	0.0106	nM	CHEMBL3686932
10.96	IC50	0.011	nM	CHEMBL3686934
10.96	Ki	0.011	nM	CHEMBL4112465
10.96	Ki	0.011	nM	CHEMBL4108340
10.96	IC50	0.011	nM	CHEMBL3686932
10.92	Ki	0.012	nM	CHEMBL3695715
10.92	Ki	0.012	nM	CHEMBL4110358
10.92	IC50	0.012	nM	CHEMBL3686915
10.92	IC50	0.012	nM	CHEMBL3686917
10.92	IC50	0.012	nM	CHEMBL3691542
10.91	IC50	0.0123	nM	CHEMBL3686915
10.91	IC50	0.0122	nM	CHEMBL3686917
10.91	IC50	0.0122	nM	CHEMBL3691542
10.89	Ki	0.013	nM	CHEMBL4111052
10.85	IC50	0.0142	nM	CHEMBL3686913
10.85	Ki	0.014	nM	CHEMBL4113752
10.85	Ki	0.014	nM	CHEMBL4107863
10.85	IC50	0.014	nM	CHEMBL3686913
10.83	IC50	0.0149	nM	CHEMBL3686930
10.82	Ki	0.015	nM	CHEMBL4110637
10.82	IC50	0.015	nM	CHEMBL3686930
10.80	IC50	0.016	nM	CHEMBL3686925
10.79	IC50	0.01625	nM	CHEMBL3686925
10.77	IC50	0.0171	nM	CHEMBL3639857
10.77	IC50	0.017	nM	CHEMBL3639857
10.72	Ki	0.019	nM	CHEMBL3665945
10.72	Ki	0.019	nM	CHEMBL3665947
10.72	Ki	0.019	nM	CHEMBL4107675
10.72	Ki	0.019	nM	CHEMBL4108308
10.72	IC50	0.019	nM	CHEMBL2180789
10.70	Ki	0.02	nM	CHEMBL3622899
10.70	Ki	0.02	nM	CHEMBL3746917
10.70	Ki	0.02	nM	CHEMBL3747450
10.70	Ki	0.02	nM	CHEMBL3659063
10.70	Ki	0.02	nM	CHEMBL4110725
10.70	Ki	0.02	nM	CHEMBL5891871
10.70	Ki	0.02	nM	CHEMBL5758106
10.70	Ki	0.02	nM	CHEMBL5845887

PubChem BioAssay actives

2647 with measured affinity, of 3283 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
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-(3-imidazo[1,2-a]pyridin-2-ylpropoxy)-5-methylpyrimidin-4-amine	1251324: Inhibition of human PDE10A2 transfected in AD293 cells by IMAP FP assay	ki	<0.0001	uM
2-[2-[7-methyl-3-(1-methylindazol-5-yl)-4-oxoquinazolin-2-yl]ethyl]isoindole-1,3-dione	1252222: Inhibition of PDE10A (unknown origin)	ki	<0.0001	uM
1,8-bis(2-fluoro-3-pyridinyl)-6-methoxy-3,4-dimethylimidazo[1,5-a]quinoxaline	1265654: Inhibition of human recombinant PDE10A1 expressed in baculovirus infected insect SF21 cells using [3H]cAMP as substrate after 30 mins by scintillation proximity assay	ic50	<0.0001	uM
1-(2-fluoro-3-pyridinyl)-6-methoxy-3,4-dimethyl-8-pyridin-3-ylimidazo[1,5-a]quinoxaline	1265654: Inhibition of human recombinant PDE10A1 expressed in baculovirus infected insect SF21 cells using [3H]cAMP as substrate after 30 mins by scintillation proximity assay	ic50	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[(2-pyrazolo[1,5-a]pyridin-2-ylcyclopropyl)methoxy]pyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-[[2-(4-methoxy-2-pyridinyl)cyclopropyl]methoxy]-5-methylpyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[[2-(1,5-naphthyridin-2-yl)cyclopropyl]methoxy]pyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[[2-(1-methylimidazol-4-yl)cyclopropyl]methoxy]pyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[[2-(4-methyl-2-pyridinyl)cyclopropyl]methoxy]pyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
2-chloro-3-methyl-N-[(1-methylpyrazol-4-yl)methyl]-6-[[(1S,2S)-2-pyridin-2-ylcyclopropyl]methoxy]pyridin-4-amine	1966138: Inhibition of human PDE10A2 transfected in human AD293 cells cytosolic fraction using cAMP as substrate by fluorescence polarization assay	ki	<0.0001	uM
N-[(3R)-1,1-dioxothiolan-3-yl]-2-[(E)-2-[3-methyl-7-(trifluoromethyl)quinoxalin-2-yl]ethenyl]-6-pyrrolidin-1-ylpyrimidin-4-amine	705199: Inhibition of PDE10A	ic50	<0.0001	uM
3-(2-phenylpyrazol-3-yl)-1-[3-(trifluoromethoxy)phenyl]pyridazin-4-one	1949361: Inhibition of full-length recombinant human PDE10A by scintillation proximity assay	ic50	<0.0001	uM
2-[2-[3-[1-(2-(18F)fluoroethyl)indazol-6-yl]-7-methyl-4-oxoquinazolin-2-yl]ethyl]-4-propan-2-yloxyisoindole-1,3-dione	1924480: Binding affinity to PDE10A (unknown origin) assessed as dissociation constant	kd	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[(2-quinolin-2-ylcyclopropyl)methoxy]pyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
2-[3-(1H-benzimidazol-2-yl)propoxy]-6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methylpyrimidin-4-amine	1251324: Inhibition of human PDE10A2 transfected in AD293 cells by IMAP FP assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-(3-quinolin-2-ylpropoxy)pyrimidin-4-amine	1251324: Inhibition of human PDE10A2 transfected in AD293 cells by IMAP FP assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[2-(1,8-naphthyridin-2-yloxy)ethoxy]pyrimidin-4-amine	1251324: Inhibition of human PDE10A2 transfected in AD293 cells by IMAP FP assay	ki	<0.0001	uM
2-methyl-6-[[(1S,2S)-2-(5-methyl-2-pyridinyl)cyclopropyl]methoxy]-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrimidin-4-amine	1966138: Inhibition of human PDE10A2 transfected in human AD293 cells cytosolic fraction using cAMP as substrate by fluorescence polarization assay	ki	<0.0001	uM
6-[[(1S,2S)-2-(5-methoxy-2-pyridinyl)cyclopropyl]methoxy]-2-methyl-N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]pyrimidin-4-amine	1966138: Inhibition of human PDE10A2 transfected in human AD293 cells cytosolic fraction using cAMP as substrate by fluorescence polarization assay	ki	<0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[[(1S,2S)-2-pyridin-2-ylcyclopropyl]methoxy]pyrimidin-4-amine	1267479: Inhibition of PDE10A (unknown origin) by IMAP assay	ki	<0.0001	uM
5-[(3R)-3-fluoropyrrolidin-1-yl]-N-(111C)methyl-2-(3-methylquinoxalin-2-yl)-N-(oxan-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine	1191635: Inhibition of human PDE10A	ic50	0.0001	uM
2-[3-(1,3-benzothiazol-2-yl)propoxy]-6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methylpyrimidin-4-amine	1251324: Inhibition of human PDE10A2 transfected in AD293 cells by IMAP FP assay	ki	0.0001	uM
6-chloro-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-5-methyl-2-[3-(1,8-naphthyridin-2-yl)propoxy]pyrimidin-4-amine	1251324: Inhibition of human PDE10A2 transfected in AD293 cells by IMAP FP assay	ki	0.0001	uM
8-bromo-1-(2-fluoro-3-pyridinyl)-6-methoxy-3,4-dimethylimidazo[1,5-a]quinoxaline	1265654: Inhibition of human recombinant PDE10A1 expressed in baculovirus infected insect SF21 cells using [3H]cAMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0001	uM
6-methoxy-3,4-dimethyl-1,8-dipyridin-3-ylimidazo[1,5-a]quinoxaline	1265654: Inhibition of human recombinant PDE10A1 expressed in baculovirus infected insect SF21 cells using [3H]cAMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0001	uM
5-[(3R)-3-fluoropyrrolidin-1-yl]-N-methyl-2-(3-methylquinoxalin-2-yl)-N-(oxan-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine;hydrochloride	1552316: Inhibition of human N-terminal FLAG-tagged PDE10A (1 to 90 residues) expressed in using African green monkey COS7 cells using [3H]cAMP or [3H]cGMP as substrate preincubated for 5 mins followed by substrate addition and measured after 30 mins by liquid scintillation counting method	ic50	0.0001	uM
5-(3-fluoropyrrolidin-1-yl)-N-(111C)methyl-2-(3-methylquinoxalin-2-yl)-N-(oxan-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine	1932344: Inhibition of PDE10A (unknown origin)	ic50	0.0001	uM
6-[[6-cyclopropyl-3-(pyrimidin-5-ylamino)pyridine-2-carbonyl]amino]-N-methyl-2-phenyl-3H-benzimidazole-5-carboxamide	1806725: PDE10A assay from Article 10.1007/s10822-022-00478-x: “A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.”	ic50	0.0001	uM
3-(2-phenylpyrazol-3-yl)-5-[3-(trifluoromethoxy)phenyl]-1H-pyridin-2-one	1949361: Inhibition of full-length recombinant human PDE10A by scintillation proximity assay	ic50	0.0001	uM
3-(2-phenylpyrazol-3-yl)-5-[3-(trifluoromethoxy)phenyl]-1H-pyrazin-2-one	1949361: Inhibition of full-length recombinant human PDE10A by scintillation proximity assay	ic50	0.0001	uM
2-[(E)-2-(3-methylquinoxalin-2-yl)ethenyl]-N-(oxan-4-yl)-6-pyrrolidin-1-ylpyrimidin-4-amine	1932344: Inhibition of PDE10A (unknown origin)	ic50	0.0001	uM
2-[2-[3-[4-((18F)fluoromethoxy)phenyl]-7-methyl-4-oxoquinazolin-2-yl]ethyl]-4-propan-2-yloxyisoindole-1,3-dione	1924480: Binding affinity to PDE10A (unknown origin) assessed as dissociation constant	kd	0.0001	uM
5-[(3R)-3-fluoropyrrolidin-1-yl]-N-(111C)methyl-N-(oxan-4-yl)-2-(5,6,7,8-tetrahydroquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidin-7-amine	1924477: Inhibition of PDE10A (unknown origin)	ic50	0.0001	uM
N-[(1-methylpyrazol-4-yl)methyl]-2-[[(1S,2S)-2-pyridin-2-ylcyclopropyl]methoxy]-1,6-naphthyridin-4-amine	1966138: Inhibition of human PDE10A2 transfected in human AD293 cells cytosolic fraction using cAMP as substrate by fluorescence polarization assay	ki	0.0001	uM
N-[(5-methyl-1,3,4-thiadiazol-2-yl)methyl]-2-[[(1S,2S)-2-pyridin-2-ylcyclopropyl]methoxy]-1,5-naphthyridin-4-amine	1966138: Inhibition of human PDE10A2 transfected in human AD293 cells cytosolic fraction using cAMP as substrate by fluorescence polarization assay	ki	0.0001	uM
N-[(1-methylpyrazol-4-yl)methyl]-2-[[(1S,2S)-2-pyridin-2-ylcyclopropyl]methoxy]-1,7-naphthyridin-4-amine	1966138: Inhibition of human PDE10A2 transfected in human AD293 cells cytosolic fraction using cAMP as substrate by fluorescence polarization assay	ki	0.0001	uM
6,8-dimethoxy-3,4-dimethyl-1-(2-methyl-3-pyridinyl)imidazo[1,5-a]quinoxaline	629788: Inhibition of N-terminal His-tagged human PDE10A expressed in Escherichia coli using [3H]cAMP after 1 hr by scintillation proximity assay	ic50	0.0001	uM
2-[2-[3-(4-methoxyphenyl)-7-methyl-4-oxopyrido[2,3-d]pyrimidin-2-yl]ethyl]-4-propan-2-yloxyisoindole-1,3-dione	705402: Inhibition of PDE10A by fluorescence polarization assay	ki	0.0001	uM
6-methoxy-3,4-dimethyl-1-(2-methyl-3-pyridinyl)-8-phenylmethoxyimidazo[1,5-a]quinoxaline	629788: Inhibition of N-terminal His-tagged human PDE10A expressed in Escherichia coli using [3H]cAMP after 1 hr by scintillation proximity assay	ic50	0.0001	uM
8-(difluoromethoxy)-6-methoxy-3,4-dimethyl-1-(2-methyl-3-pyridinyl)imidazo[1,5-a]quinoxaline	629788: Inhibition of N-terminal His-tagged human PDE10A expressed in Escherichia coli using [3H]cAMP after 1 hr by scintillation proximity assay	ic50	0.0001	uM
2-[2-[3-(4-methoxyphenyl)-4-oxoquinazolin-2-yl]ethyl]-4-pyridin-4-ylisoindole-1,3-dione	1252222: Inhibition of PDE10A (unknown origin)	ki	0.0001	uM
6-methoxy-3,4-dimethyl-1-(3-methyl-4-pyridinyl)-8-(trifluoromethyl)imidazo[1,5-a]quinoxaline	629788: Inhibition of N-terminal His-tagged human PDE10A expressed in Escherichia coli using [3H]cAMP after 1 hr by scintillation proximity assay	ic50	0.0001	uM
2-[2-[3-(4-methoxyphenyl)-4-oxoquinazolin-2-yl]ethyl]-4-propan-2-yloxyisoindole-1,3-dione	1252222: Inhibition of PDE10A (unknown origin)	ki	0.0001	uM
4-(azetidine-1-carbonyl)-1-methyl-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)pyrazole-5-carboxamide	705177: Inhibition of PDEDA2 using [3H]cGMP as substrate after 30 mins by scintillation proximity assay	ic50	0.0001	uM
1-methyl-4-(morpholine-4-carbonyl)-N-(2-phenylimidazo[1,2-a]pyridin-7-yl)pyrazole-5-carboxamide	1615594: Inhibition of human PDE10	ic50	0.0001	uM
4-(azetidine-1-carbonyl)-N-(6-bromo-2-phenylimidazo[1,2-a]pyridin-7-yl)-1-methylpyrazole-5-carboxamide	1615594: Inhibition of human PDE10	ic50	0.0001	uM
6-cyclopropyl-N-[1-(2-hydroxyethyl)-3-quinolin-2-ylpyrazol-5-yl]-3-(pyrimidin-5-ylamino)pyridine-2-carboxamide	1806725: PDE10A assay from Article 10.1007/s10822-022-00478-x: “A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.”	ic50	0.0001	uM
6-cyclopropyl-N-(1-methyl-3-quinolin-2-ylpyrazol-5-yl)-3-(pyrimidin-5-ylamino)pyridine-2-carboxamide	1806725: PDE10A assay from Article 10.1007/s10822-022-00478-x: “A high quality, industrial data set for binding affinity prediction: performance comparison in different early drug discovery scenarios.”	ic50	0.0001	uM
4-[6-methoxy-3,4-dimethyl-1-(2-methyl-3-pyridinyl)imidazo[1,5-a]quinoxalin-8-yl]morpholine	629788: Inhibition of N-terminal His-tagged human PDE10A expressed in Escherichia coli using [3H]cAMP after 1 hr by scintillation proximity assay	ic50	0.0001	uM
1-(cyclopropylmethyl)-4-fluoro-5-[5-methoxy-4-oxo-3-(2-phenylpyrazol-3-yl)pyridazin-1-yl]-3,3-dimethylindol-2-one	1254107: Inhibition of human PDE10A2 expressed in COS-7 cells using [3H]cGMP as substrate assessed as substrate hydrolysis after 60 mins by scintillation proximity assay	ic50	0.0001	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases expression	6
trichostatin A	affects cotreatment, decreases expression, increases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
2-((4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy)methyl)quinoline	decreases expression, decreases activity	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Cadmium	increases abundance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
p-Chloromercuribenzoic Acid	decreases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
bufotalin	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation, increases methylation	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	affects methylation	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
clothianidin	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1

ChEMBL screening assays

357 unique, capped per target: 345 binding, 9 admet, 3 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
CHEMBL5723185	Functional	Affinity Biochemical interaction: (inhibition of enzyme activity with [3H]cGMP or [3H]cAMP as the substrate) EUB0002477a PDE10A	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C0TF	ACTOne cAMP-PDE10A	Transformed cell line	Female
CVCL_E4Q6	KOLF2.1J PDE10A 71.8kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_TC63	HAP1 PDE10A (-) 1	Cancer cell line	Male
CVCL_TC64	HAP1 PDE10A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
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