PDE10A explained

cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A is an enzyme that in humans is encoded by the PDE10A gene.^{[1] [2]}

Various cellular responses are regulated by the second messengers cAMP and cGMP. Phosphodiesterases, such as PDE10A, eliminate cAMP- and cGMP-mediated intracellular signaling by hydrolyzing the cyclic nucleotide to the corresponding nucleoside 5-prime monophosphate.^{[2] [3]}

Inhibitors

• Compound 96: IC₅₀ = 700 pM, high selectivity against all other members of the PDE family
• Papaverine^[4]
• PF-2545920^[5]
• TAK-063: IC₅₀ = 300 pM^[6]
• AMG 579^[7]
• CPL500036^[8]

Research

Preliminary evidence indicates a possible link between PDE10A expression and obesity in mice and humans.^[9] PDE10A is a regulatory protein involved in the signaling of the striatum, a region of the brain important for controlling movement and cognition. Dysfunction of the striatum has been linked to the development of schizophrenia. Inhibition of PDE10A has been identified as a potential treatment for the disorder, and an inhibitor compound (MK-8189) is as of February 2023 in Phase 2b clinical development for the treatment of schizophrenia.^[10]

Further reading

• Loughney K, Snyder PB, Uher L, Rosman GJ, Ferguson K, Florio VA . Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase . Gene . 234 . 1 . 109–117 . June 1999 . 10393245 . 10.1016/S0378-1119(99)00171-7 .
• Kotera J, Fujishige K, Yuasa K, Omori K . Characterization and phosphorylation of PDE10A2, a novel alternative splice variant of human phosphodiesterase that hydrolyzes cAMP and cGMP . Biochemical and Biophysical Research Communications . 261 . 3 . 551–557 . August 1999 . 10441464 . 10.1006/bbrc.1999.1013 .
• Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S . HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway . FASEB Journal . 15 . 2 . 483–491 . February 2001 . 11156964 . 10.1096/fj.00-0354com . free . 26315564 .
• Frame M, Wan KF, Tate R, Vandenabeele P, Pyne NJ . The gamma subunit of the rod photoreceptor cGMP phosphodiesterase can modulate the proteolysis of two cGMP binding cGMP-specific phosphodiesterases (PDE6 and PDE5) by caspase-3 . Cellular Signalling . 13 . 10 . 735–741 . October 2001 . 11602184 . 10.1016/S0898-6568(01)00193-0 .
• Gross-Langenhoff M, Hofbauer K, Weber J, Schultz A, Schultz JE . cAMP is a ligand for the tandem GAF domain of human phosphodiesterase 10 and cGMP for the tandem GAF domain of phosphodiesterase 11 . The Journal of Biological Chemistry . 281 . 5 . 2841–2846 . February 2006 . 16330539 . 10.1074/jbc.M511468200 . free .
• Chappie TA, Helal CJ, Hou X . Current landscape of phosphodiesterase 10A (PDE10A) inhibition . Journal of Medicinal Chemistry . 55 . 17 . 7299–7331 . September 2012 . 22834877 . 10.1021/jm3004976 .

Notes and References

1. Fujishige K, Kotera J, Michibata H, Yuasa K, Takebayashi S, Okumura K, Omori K . Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A) . The Journal of Biological Chemistry . 274 . 26 . 18438–18445 . June 1999 . 10373451 . 10.1074/jbc.274.26.18438 . free .
2. Web site: Entrez Gene: PDE10A phosphodiesterase 10A.
3. Fujishige K, Kotera J, Yuasa K, Omori K . The human phosphodiesterase PDE10A gene genomic organization and evolutionary relatedness with other PDEs containing GAF domains . European Journal of Biochemistry . 267 . 19 . 5943–5951 . October 2000 . 10998054 . 10.1046/j.1432-1327.2000.01661.x . free .
4. Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, Schmidt CJ . 6 . Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis . Neuropharmacology . 51 . 2 . 386–396 . August 2006 . 16780899 . 10.1016/j.neuropharm.2006.04.013 . 13447370 .
5. Verhoest PR, Chapin DS, Corman M, Fonseca K, Harms JF, Hou X, Marr ES, Menniti FS, Nelson F, O'Connor R, Pandit J, Proulx-Lafrance C, Schmidt AW, Schmidt CJ, Suiciak JA, Liras S . 6 . 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 . Journal of Medicinal Chemistry . 52 . 16 . 5188–5196 . August 2009 . 19630403 . 10.1021/jm900521k .
6. Kunitomo J, Yoshikawa M, Fushimi M, Kawada A, Quinn JF, Oki H, Kokubo H, Kondo M, Nakashima K, Kamiguchi N, Suzuki K, Kimura H, Taniguchi T . 6 . Discovery of 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063), a highly potent, selective, and orally active phosphodiesterase 10A (PDE10A) inhibitor . Journal of Medicinal Chemistry . 57 . 22 . 9627–9643 . November 2014 . 25384088 . 10.1021/jm5013648 .
7. Hu E, Chen N, Bourbeau MP, Harrington PE, Biswas K, Kunz RK, Andrews KL, Chmait S, Zhao X, Davis C, Ma J, Shi J, Lester-Zeiner D, Danao J, Able J, Cueva M, Talreja S, Kornecook T, Chen H, Porter A, Hungate R, Treanor J, Allen JR . 6 . Discovery of clinical candidate 1-(4-(3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazin-2-yl)piperidin-1-yl)ethanone (AMG 579), a potent, selective, and efficacious inhibitor of phosphodiesterase 10A (PDE10A) . Journal of Medicinal Chemistry . 57 . 15 . 6632–6641 . August 2014 . 25062128 . 10.1021/jm500713j .
8. Matloka M, Janowska S, Pankiewicz P, Kokhanovska S, Kos T, Hołuj M, Rutkowska-Wlodarczyk I, Abramski K, Janicka M, Jakubowski P, Świątkiewicz M, Welniak-Kaminska M, Hucz-Kalitowska J, Dera P, Bojarski L, Grieb P, Popik P, Wieczorek M, Pieczykolan J . 6 . A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects . Frontiers in Pharmacology . 13 . 999685 . 2022 . 36438799 . 9681820 . 10.3389/fphar.2022.999685 . free .
9. Hankir MK, Kranz M, Gnad T, Weiner J, Wagner S, Deuther-Conrad W, Bronisch F, Steinhoff K, Luthardt J, Klöting N, Hesse S, Seibyl JP, Sabri O, Heiker JT, Blüher M, Pfeifer A, Brust P, Fenske WK . 6 . A novel thermoregulatory role for PDE10A in mouse and human adipocytes . EMBO Molecular Medicine . 8 . 7 . 796–812 . July 2016 . 27247380 . 4931292 . 10.15252/emmm.201506085 .
10. Layton ME, Kern JC, Hartingh TJ, Shipe WD, Raheem I, Kandebo M, Hayes RP, Huszar S, Eddins D, Ma B, Fuerst J, Wollenberg GK, Li J, Fritzen J, McGaughey GB, Uslaner JM, Smith SM, Coleman PJ, Cox CD . 6 . Discovery of MK-8189, a Highly Potent and Selective PDE10A Inhibitor for the Treatment of Schizophrenia . Journal of Medicinal Chemistry . 66 . 2 . 1157–1171 . January 2023 . 36624931 . 9884086 . 10.1021/acs.jmedchem.2c01521 .