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phosphodiesterase 10A

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Target not currently curated in GtoImmuPdb

Target id: 1310

Nomenclature: phosphodiesterase 10A

Abbreviated Name: PDE10A

Family: Phosphodiesterases, 3',5'-cyclic nucleotide (PDEs)

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 779 6q27 PDE10A phosphodiesterase 10A
Mouse - 790 17 A1 Pde10a phosphodiesterase 10A
Rat - 794 1q12 Pde10a phosphodiesterase 10A
Previous and Unofficial Names Click here for help
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A | testis-specific phosphodiesterase PDE10A2
Database Links Click here for help
Alphafold Q9Y233 (Hs), Q8CA95 (Mm), Q9QYJ6 (Rn)
BRENDA 3.1.4.17
CATH/Gene3D 3.30.450.40, 1.10.1300.10
ChEMBL Target CHEMBL4409 (Hs), CHEMBL1795126 (Mm), CHEMBL6140 (Rn)
DrugBank Target Q9Y233 (Hs)
Ensembl Gene ENSG00000112541 (Hs), ENSMUSG00000023868 (Mm), ENSRNOG00000011310 (Rn)
Entrez Gene 10846 (Hs), 23984 (Mm), 63885 (Rn)
Human Protein Atlas ENSG00000112541 (Hs)
KEGG Enzyme 3.1.4.17
KEGG Gene hsa:10846 (Hs), mmu:23984 (Mm), rno:63885 (Rn)
OMIM 610652 (Hs)
Pharos Q9Y233 (Hs)
SynPHARM 84439 (in complex with PF-2545920)
UniProtKB Q9Y233 (Hs), Q8CA95 (Mm), Q9QYJ6 (Rn)
Wikipedia PDE10A (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of human PDE10A in complex with the selective inhibitor PF-2545920.
PDB Id:  3HR1
Ligand:  mardepodect
Resolution:  1.53Å
Species:  Human
References:  6
Enzyme Reaction Click here for help
EC Number: 3.1.4.17
Rank order of affinity (Human)
cyclic AMP, cyclic GMP  [2]

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
MK-8189 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 10.5 pKi 4
⤷ pKi 10.5 (Ki 2.9x10-11 M) [4]
compound 19 [PMID: 22142545] Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 9.0 pKi 8
⤷ pKi 9.0 (Ki 1x10-9 M) [8]
compound 27 [PMID: 22142545] Small molecule or natural product Primary target of this compound Hs Inhibition 8.3 pKi 8
⤷ pKi 8.3 (Ki 5x10-9 M) [8]
mardepodect Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Inhibition 9.4 pIC50 6
⤷ pIC50 9.4 (IC50 3.7x10-10 M) [6]
PBF-999 Small molecule or natural product Hs Inhibition 8.2 pIC50 3
⤷ pIC50 8.2 (IC50 5.8x10-9 M) [3]
TC-E 5005 Small molecule or natural product Ligand has a PDB structure Hs Inhibition 8.1 pIC50 5
⤷ pIC50 8.1 (IC50 7.3x10-9 M) [5]
papaverine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 – 7.8 pIC50 1,10
⤷ pIC50 7.8 (IC50 1.7x10-8 M) [1]
pIC50 7.7 (IC50 2.1x10-8 M) [10]
PDE4 inhibitor 16 Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.0 pIC50 9
⤷ pIC50 6.0 (IC50 9.2x10-7 M) [9]
Description: Inhibition of enzymatic activity of the recombinant human PDE10A catalytic domain in vitro.
Tissue Distribution Click here for help
PDE10A is highly enriched in the brain, and shows a unique expression profile in brain regions that suggest potential for novel antipsychotic (schzophrenia) treatments, and for other disorders affecting the basal ganglia (e.g. bipolar and autism spectrum disorders, and movement disorders such as Parkinson's and Huntington's diseases).
Species:  Human
Technique: 
References:  7

References

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1. Asproni B, Murineddu G, Pau A, Pinna GA, Langgård M, Christoffersen CT, Nielsen J, Kehler J. (2011) Synthesis and SAR study of new phenylimidazole-pyrazolo[1,5-c]quinazolines as potent phosphodiesterase 10A inhibitors. Bioorg Med Chem, 19 (1): 642-9. [PMID:21087867]

2. Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K. (1999) Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J Biol Chem, 274 (26): 18438-45. [PMID:10373451]

3. Gomez JC, laria JCP. (2016) Pyrimidine derivatives as phosphodiesterase 10 inhibitors (PDE-10). Patent number: US9447095B2. Assignee: Palobiofarma SL. Priority date: 24/01/2014. Publication date: 20/09/2016.

4. Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B et al.. (2023) Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia. J Med Chem, 66 (2): 1157-1171. [PMID:36624931]

5. Malamas MS, Ni Y, Erdei J, Stange H, Schindler R, Lankau HJ, Grunwald C, Fan KY, Parris K, Langen B et al.. (2011) Highly potent, selective, and orally active phosphodiesterase 10A inhibitors. J Med Chem, 54 (21): 7621-38. [PMID:21988093]

6. Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, Marr ES, Menniti FS, Nelson F, O'Connor R et al.. (2009) Discovery of a novel class of phosphodiesterase 10A inhibitors and identification of clinical candidate 2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]-quinoline (PF-2545920) for the treatment of schizophrenia. J Med Chem, 52 (16): 5188-96. [PMID:19630403]

7. Wilson LS, Brandon NJ. (2015) Emerging biology of PDE10A. Curr Pharm Des, 21 (3): 378-88. [PMID:25159072]

8. Yang SW, Smotryski J, McElroy WT, Tan Z, Ho G, Tulshian D, Greenlee WJ, Guzzi M, Zhang X, Mullins D et al.. (2012) Discovery of orally active pyrazoloquinolines as potent PDE10 inhibitors for the management of schizophrenia. Bioorg Med Chem Lett, 22 (1): 235-9. [PMID:22142545]

9. Zhang X, Dong G, Li H, Chen W, Li J, Feng C, Gu Z, Zhu F, Zhang R, Li M et al.. (2019) Structure-Aided Identification and Optimization of Tetrahydro-isoquinolines as Novel PDE4 Inhibitors Leading to Discovery of an Effective Antipsoriasis Agent. J Med Chem, 62 (11): 5579-5593. [PMID:31099559]

10. Zhang Z, Lu X, Xu J, Rothfuss J, Mach RH, Tu Z. (2011) Synthesis and in vitro evaluation of new analogues as inhibitors for phosphodiesterase 10A. Eur J Med Chem, 46 (9): 3986-95. [PMID:21705115]

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