PDE10A inhibitors: Novel therapeutic drugs for schizophrenia

Current Pharmaceutical Design

Volumn 17, Issue 2, 2011, Pages 137-150

  Kehler, Jan ^a   Nielsen, Jacob ^a  

^a H LUNDBECK A S   (Denmark)

Author keywords

Antipsychotic; Basal ganglia; cAMP PKG; cGMP PKG; Dopamine; PDE10A; PDE10A structure; Phosphodiesterase 10A; Pro cognitive; Psychosis; Schizophrenia; Signalling cascades; Striatonigral; Striatopallidal

Indexed keywords

2 [4 [1 METHYL 4 (4 PYRIDINYL) 3 PYRAZOLYL]PHENOXYMETHYL]QUINOLINE; CYCLIC AMP; CYCLIC GMP; DOPAMINE 1 RECEPTOR; DOPAMINE 2 RECEPTOR; PAPAVERINE; PHOSPHODIESTERASE; PHOSPHODIESTERASE 10A; PHOSPHODIESTERASE 10A INHIBITOR; PHOSPHODIESTERASE INHIBITOR; TP 10; UNCLASSIFIED DRUG;

ARTICLE; BASAL GANGLION; ENZYME INHIBITION; ENZYME LOCALIZATION; ENZYME STRUCTURE; HUMAN; IC 50; NEUROBIOLOGY; NONHUMAN; PRIORITY JOURNAL; SCHIZOPHRENIA; SIGNAL TRANSDUCTION; STRUCTURE ACTIVITY RELATION;

ANIMALS; BASAL GANGLIA; CLINICAL TRIALS AS TOPIC; CYCLIC AMP-DEPENDENT PROTEIN KINASES; HUMANS; MICE; MOLECULAR TARGETED THERAPY; PHOSPHODIESTERASE INHIBITORS; PHOSPHORIC DIESTER HYDROLASES; RATS; RECEPTORS, DOPAMINE D1; SCHIZOPHRENIA; SIGNAL TRANSDUCTION;

EID: 79953296930     PISSN: 13816128     EISSN: None     Source Type: Journal    
DOI: 10.2174/138161211795049624     Document Type: Article

References (125)

1. For some reviews see a) Boswell-Smith V et al. Phosphodiesterase inhibitors. Br. J. Pharmacol. 2006; 147 (Suppl. 1), 252-257.
2. Jeon YH, Heo YS, Kim CM, Hyun YL, Lee TG, Ro S and Cho JM. Phosphodiesterase: overview of protein structures, potential therapeutic applications and recent progress in drug development. Cell. Mol. Life Sci. 2005; 62: 1198-1220.
3. Francis S, Corbin J. Cyclic nucleotide-dependent protein kinases: Intracellular receptors for cAMP and cGMP action. Crit. Rev. Clin. Lab. Sci. 1999; 36(4):275-328.
4. Kaupp UB, Seifert R. Cyclic nucleotide-gated ion channels. Physiol. Rev. 2002; 82(3):769-824.
5. Bos JL. EPAC proteins: Multi-purpose cAMP targets. Trends Biochem. Sci. 2006; 31(12):680-686.
6. Hanoune, J, Defer N. Regulation and role of adenylyl cyclase isoforms. Annu. Rev. Pharmacol. Toxicol. 2001; 41:145-174.
7. Missale C, Nash R, Robinson S, Jaber M, Caron M. Dopamine receptors: from structure to function, Physiol. Rev. 1998; 78 (1): 189-225.
8. Guevara-Guzmán R, Emson R, Kendrick K. Modulation of in vivo striatal transmitter release by nitric oxide and cyclic GMP. J. Neurochem. 1994; 62: 807-810.
9. Tsou K, Snyder G, Greengard P. Nitric oxide/cGMP pathway stimulates phosphorylation of DARPP-32, a dopamineand cAMP-regulated phosphoprotein, in the substantia nigra. Proc. Natl. Acad. Sci. U.S.A. 1993; 90: 3462-3465.
10. Marte A, Pepicelli O, Cavallero A, Raiteri M, Fedele E. In vivo effects of phosphodiesterase inhibition on basal cyclic guanosine monophosphate levels in the prefrontal cortex, hippocampus and cerebellum of freely moving rats, J. Neurosci. Res. 2008; 86: 3338-3347.
11. Piedrafita B, Cauli O, Montoliu C, Vicente F. The function of the glutamate-nitric oxide-cGMP pathway in brain in vivo and learning ability decrease in parallel in mature compared with young rats. Learn.Mem. 2007; 14: 254-258.
12. Baillie GS. Compartmentalized signalling: spatial regulation of cAMP by the action of compartmentalized phosphodiesterases. FEBS J. 2009;276(7):1790-9.
13. Houslay MD. Underpinning compartmentalised cAMP signaling through targeted cAMP breakdown. Trends Biochem. Sci. 2010; 35: 91-100.
14. Menniti FS, Faraci WS, Schmidt CJ. Phosphodiesterases in the CNS: Targets for drug development. Nat. Rev. Drug. Discov. 2006; 5(8):660-670.
15. Strick CA, Schmidt CJ, Menniti FS. PDE10A: A striatum enriched, dual-substrate phosphodiesterase. In: Cyclic Nucleotide Phosphodiesterases in Health and Disease. Beavo JA, Francis SH, Houslay MD (Eds), CRC Press 2006:237-254.
16. Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59: 367-374.
17. Fujishige K, Kotera J, Michibata H, et al. Cloning and characterization of a novel human phosphodiesterase that hydrolyzes both cAMP and cGMP (PDE10A). J. Biol. Chem. 1999; 274:18438-18445.
18. Fujishige K, Kotera J, Omori K. Striatum-and testis-specific phosphodiesterase PDE10A isolation and characterization of a rat PDE10A. Eur. J. Biochem. 1999; 266:1118-1127.
19. 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 1999; 261: 551-557.
20. Loughney K, Snyder PB, Uher L, Rosman GI, Ferguson K, Florio VA. Isolation and characterization of PDE10A, a novel human 3', 5'-cyclic nucleotide phosphodiesterase. Gene 1999; 234:109-117.
21. Soderling SH, Bayuga SJ, Beavo A. Isolation and characterization of a dual-substrate phosphodiesterase gene family: PDE10A. Proc Natl Acad Sci USA 1999; 96:7071-7076.
22. Beavo JA, Brunton LL. Cyclic nucleotide research-Still expanding after half a century. Nat. Rev. Mol. Cell. Biol. 2002; 3(9):710-718.
23. Conti M, Beavo J. Biochemistry and physiology of cyclic nucleotide phosphodiesterases: Essential components in cyclic nucleotide signaling. Ann. Rev. Biochem. 2007; 76(1):481-511.
24. Strick CA, Schmidt CJ, Menniti FS: PDE10A: A striatum enriched, dual-substrate phosphodiesterase. In: Cyclic Nucleotide Phosphodiesterases in Health and Disease. Francis S, Housley M, Beavo J (Eds), CRC Press, Boca Raton, FL, USA (2006).
25. Kotera J, Sasaki T, Kobayashi T, Fujishige K, Yamashita Y, Omori K. Subcellular localization of cyclic nucleotide phosphodiesterase type 10A variants, and alteration of the localization by cAMP-dependent protein kinase-dependent phosphorylation. J. Biol. Chem. 2004; 279:366-4375.
26. Wang H, Liu Y, Hou J et al.: Structural insight into substrate specificity of phosphodiesterase 10. Proc. Natl. Acad. Sci. USA 2007; 104:5782-5787.
27. Andersen OA, Schönfeld DL, Toogood-Johnson I, Felicetti B, Albrecht C, Fryatt T, Whittaker M, Halletta D and Barkera J. Cross-linking of protein crystals as an aid in the generation of binary protein-ligand crystal complexes, exemplified by the human PDE10a-papaverine structure. Acta Cryst. 2009: D65, 872-874.
28. Chappie TA, Humphrey JM, Allen MP et al.: Discovery of a series of6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors. J. Med. Chem. 2007; 50:182-185.
29. Verhoest PR, Chapin DS, Corman M et al.: 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. 2009; 52: 5188-5196.
30. Höfgen N, Stange H, Schindler R, et al.: Discovery of Imidazo[1,5a]pyrido-[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitors. J. Med. Chem. 2010; 53: 4399-4411.
31. Pandit J. Crystal Structure of 3', 5'-Cyclic Nucleotide Phosphodiesterase(PDE10A) and Uses Thereof; Pfizer, Inc.: US 2005/0202550, 2005.
32. Benz J. Phosphodiesterase10 catalytic domain crystals, F.Hoffmann-LaRoche AG. WO 2009/090004, 2009.
33. Card GL, England BP, Suzuki Y, et al.: Structural basis for the activity of drugs that inhibit phosphodiesterases. Structure 2004; 12:2233-2247.
34. Manallack DT, Hughes RA, Thompson PE: The next generation of phosphodiesterase inhibitors: Structural clues to ligand and substrate selectivity of phosphodiesterases. J. Med. Chem. 2005; 48:3449-3462.
35. Lau JK, Li XB, Cheng YK. A Substrate Selectivity and Inhibitor Design Lesson from the PDE10-cAMP Crystal Structure: A Computational Study. J. Phys. Chem. B 2010; 114: 5154-5160.
36. Lu H, Goren AC, Zhan CG. Characterization of the tructures of Phosphodiesterase10Binding with Adenosine3',5'-Monophosphate and Guanosine 3',5'-Monophosphate by Hybrid Quantum Mechanical/Molecular Mechanical Calculations. J. Phys. Chem. B 2010; 114: 7022-7028.
37. Schmidtke P, Barril X. Understanding and Predicting Druggability. A High-Throughput Method for Detection of Drug Binding Sites. J. Med. Chem. 2010; 53, 5858-5867.
38. Zhang KY, Card GL, Suzuki Y, Artis DR, Fong D, Gillette S, Hsieh D, 42. Neiman J, West BL, Zhang C, Milburn MV et al: A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. Molecular Cell 2004; 15(2):279-286.
39. Ke H, Wang H. Crystal Structures of Phosphodiesterases and Implications on Substrate Specificity and Inhibitor Selectivity. Current Topics in Medicinal Chemistry, 2007; 7: 391-403.
40. Wang H, Robinson H, Ke H: 46. The molecular basis for different recognition of substrates by phosphodiesterase families 4 and 10. J. Mol. Biol. 2007; 371(2):302-307.
41. Yabuuchi K, Kuroiwa M, Shuto T, Sotogaku N, Snyder GL, Higashi, H, Tanaka M, Greengard P, Nishi A. Role of adenosine a1 receptors in the modulation of dopamine d1 and adenosine a2a receptor signaling in the neostriatum. Neuroscience 2006; 141:19-25.
42. Handa N, Mizohata E, Kishishita S, Toyama M, Morita S, Uchikubo-Kamo T, Akasaka R, Omori K, Kotera J, Terada T, Shirouzu M et al: Crystal structure of the GAF-B domain from human phosphodiesterase 10A complexed with its ligand, cAMP. J Biol Chem (2008) 283(28):19657-19664.
43. Zoraghi R, Corbin JD, Francis SH. Properties and Functions of GAF Domains in Cyclic Nucleotide Phosphodiesterases and Other Proteins. Mol Pharmacol 2004; 65:267-278.
44. 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. J. Biol. Chem. 2006; 281(5): 2841-2846.
45. Matthiesen K, Nielsen J. Binding of cyclic nucleotides to phosphodiesterase 10A and 11A GAF domains does not stimulate catalytic activity. Biochem J. 2009; 12; 423:401-9.
46. Lakics V, Karran EH, Boess FG. Quantitative comparison of phosphodiesterase mRNA distribution in human brain and peripheral tissues. Neuropharmacology 2010; 59:367-374.
47. Seeger TF, Bartlett B, Coskran TM, et al: Immunohistochemical localization of PDE10A in the rat brain. Brain Research 2003; 985:113-126.
48. Coskran TM, Morton D, Menniti FS, et al.: Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J. Histochem Cytochem. 2006; 54:1205-1213.
49. Xie Z, Adamowicz WO, Eldred WD, et al. Cellular and subcellular localization of PDE10A, a striatum-enriched phosphodiesterase. Neuroscience 2006; 139:597-607.
50. Charych EI, Jiang LX, Lo F, Sullivan K, Brandon NJ. Interplay of Palmitoylation and Phosphorylation in the Trafficking and Localization of Phosphodiesterase 10A: Implications for the Treatment of Schizophrenia. J. Neuroscience 2010; 30(27):9027-9037.
51. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, Ma G, Bupp S, hrestha P, Shah RD, Doughty ML, Gong S, Greengard P, Heintz N (2008) Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:749-762.
52. For recent reviews concerning function of the basal ganglia circuit see: a) Handbook of Basal Ganglia Structure and Function, Ed. Steiner H, Tseng KY. in Handbook of Behavioral Neuroscience, 2010;20:3-693, Academic Press, London.
53. Ashby FG, Turner BO and Horvitz JC. Cortical and basal ganglia contributions to habit learning and automaticity, Trends in Cognitive Sciences 2010, 14: 208-215.
54. Haber SN and Knutson B. The Reward Circuit: Linking Primate Anatomy and Human Imaging, Neuropsychopharmacology Reviews 2010; 35: 4-26.
55. Grahna JA, Parkinson JA, Owena AM. The role of the basal ganglia in learning and memory: Neuropsychological studies, Behavioural Brain Research 2009; 199: 53-60.
56. DeLong MR, Wichmann T. Circuits and Circuit Disorders of the Basal Ganglia. Arch Neurol. 2007; 64:20-24.
57. Kreitzerl AC, Malenka RC. Striatal Plasticity and Basal Ganglia Circuit Function. Neuron 2008; 60: 543-554.
58. Emson PC, Waldvogel HJ. Chapter 4-Neurotransmitter Receptors in the Basal Ganglia. In Handbook of Behavioral Neuroscience, Academic Press, London, 2010, 20: 75-96.
59. Versteega DHG, Gugtena JVD, Jonga WD and Palkovitsa M, Regional concentrations of noradrenaline and dopamine in rat brain. Brain Research 1976; 113: 563-574
60. Gerfen, CR. Basal Ganglia. In: Paxinos, G., editor. The Rat Nervous System. Elsevier Academic Press; Amsterdam: 2004. p. 445-508.
61. Moustafa AA, Shermanb SJ, Franka M. A dopaminergic basis for working memory, learning and attentional shifting in Parkinsonism. Neuropsychologia 46 (2008) 3144-3156.
62. P. Greengard, The neurobiology of slow synaptic transmission, Science 2001; 294 (5544):1024-1030.
63. Nishi A, Kuroiwa M, Miller D, O'Callaghan J, Bateup H, Shuto T, Sotogaku N, Fukuda T, Heintz N, Greengard P, Snyder G, Distinct roles of PDE4 and PDE10A in the regulation of cAMP/PKA signaling in the striatum. J. Neurosci. 2008; 28:10460-10471.
64. West A, Grace A. The nitric oxide-guanylyl cyclase signaling pathway modulates membrane activity states and electrophysiological properties of striatal medium spiny neurons recorded in vivo, J. Neurosci. 24 (2004) 1924-1935.
65. Lin DS, Fretier P, Jiang C, Vincent SR. Nitric Oxide Signaling via cGMP-Stimulated Phosphodiesterase in Striatal Neurons. Synapse 2010; 64:460-466.
66. Schmidt CJ, Chapin DS, Cianfrogna J, Corman ML, Hajos M, Harms JF, Hoffman WE, Lebel LA, McCarthy SA, Nelson FR, Proulx-LaFrance C et al: Preclinical characterization of selective phosphodiesterase 10A inhibitors: A new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther (2008) 325(2):681-690.
67. Verhoest PR, Chapin DS, Corman M et al.: 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. 2009; 52(16): 5188-5196.
68. Grauer SM, Pulito VL, Navarra RL et al.: PDE10A Inhibitor Activity in Preclinical Models of the Positive, Cognitive and Negative Symptoms of Schizophrenia. J. Pharmacol. Exp. Ther. 2009; 331:574-590.
69. http://clinicaltrials.gov/ct2/results?term=PF-02545920. Pfizer has been developing PF-2545920 (MP-10) for the potential oral treatment of schizophrenia. MP-10 entered phase I in October 2006, a placebo-controlled, randomized, double-blind, parallel assignment, safety/efficacy phase I trial was initiated in subjects (expected n = 40) with schizophrenia. The primary endpoint was safety and pharmacokinetics. The study completed in May 2007. In August 2008, data was presented from this trial at the 236th ACS National Meeting in Philadelphia, PA. MP-10 demonstrated a clearance of 4 ml/min/kg, a half-life of 14 h, high oral bioavailability and low pharmacokinetic variability. Phase 2 was initiated in December 2007, a randomized, double-blind, parallel assignment trial was initiated in subjects (expected n = 54) with schizophrenia in the US. The subjects were to receive 15 mg oral tablet of PF-2545920 bid or placebo bid for 21 days. The primary endpoint was change from baseline to endpoint on the Positive and Negative Symptom Assessment Scale (PANSS) and safety. The study was scheduled to complete in May 2008; by February 2008, the trial had been terminated (n=35). There is no information as to why Pfizer stopped the phase 2 trial. According to company website Pfizer is currently progressing MP10 in a new phase 2. There is no information released as to what Pfizer plan to do differently in the second trial.
70. Höfgen N, Stange H, Schindler R, Lankau HJ, Grunwald C, Langen B, Egerland U, Tremmel P, Pangalos MN, Marquis KL, Hage T, Harrison BL, Malamas MS, Brandon NJ, Kronbach T. Discovery of Imidazo[1,5-a]pyrido[3,2-e]pyrazines as a New Class of Phosphodiesterase 10A Inhibitiors. J. Med. Chem. 2010, 53, 4399-4411.
71. Chappie TA, Humphrey JM, Allen MP, Estep KG, Fox CB, Lebel LA, Liras S, Marr ES, Menniti FS, Pandit J, Schmidt CJ et al: Discovery of a series of 6,7-dimethoxy-4-pyrrolidylquinazoline PDE10A inhibitors. J. Med. Chem. 2007; 50(2):182-185.
72. Cantin LD, Magnuson S, Gunn D, Barucci N, Breuhaus M, Bullock WH, Burke J, Thomas H. Claus TH, Daly M, DeCarr L, Gore-Willse A, Hoover-Litty H, Kumarasinghe ES, Li Y, Liang SX, Livingston JN, Lowinger T, MacDougall M, Ogutu HO, Olague A, Ott-Morgan R, Schoenleber RW, Tersteegen A, Wickens P, Zhang Z, Zhu J, Zhua L, Sweet LJ. PDE-10A inhibitors as insulin secretagogues. Bioorg. Med. Chem. Lett. 2007; 17:2869-2873
73. Siuciak JA. The role of phosphodiesterases in schizophrenia: therapeutic implications. CNS Drugs. 2008; 22:983-993.
74. Siuciak JA, Chapin DS, Harms JF, Lebel LA, McCarthy SA, Chambers L, Shrikhande A, Wong S, Menniti FS, and Schmidt CJ Inhibition of the striatum-enriched phosphodiesterase PDE10A: a novel approach to the treatment of psychosis. Neuropharmacology 2006; 51:386-396.
75. Siuciak JA, McCarthy SA, Chapin DS, Fujiwara RA, James LC, Williams RD, Stock JL, McNeish JD, Strick CA, Menniti FS, et al. Genetic deletion of the striatum-enriched phosphodiesterase PDE10A: evidence for altered striatal function. 2006; Neuropharmacology 51:374-385.
76. Nishi A, Snyder GL. Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibitionin Dopaminergic Neurotransmission J. Pharmacol. Sci. 2010; 114: 6-16.
77. Torremans A, Ahnaou A, Van Hemelrijck A, Straetemans R, Geys H, Vanhoof G, Meert TF, Drinkenburg WH. Effects of phosphodiesterase 10 inhibition on striatal cyclic AMP and peripheral physiology in rats. Acta Neurobiol. Exp. 2010; 70: 13-19.
78. Weber M, Breier M, Ko D et al.: Evaluating the antipsychotic profile of the preferential PDE10A inhibitor, papaverine. Psychopharmacology 2009; 203(4):723-735.
79. Celen S, Koole M, De Angelis M, Sannen I, Chitneni SK, Alcazar J, Dedeurwaerdere S, Moechars D, Schmidt M, Verbruggen A, Langlois X, Van Laere K, Andrés JI, Bormans G. Preclinical Evaluation of 18F-JNJ41510417 as a Radioligand for PET Imaging of Phosphodiesterase-10A in the Brain. J. Nucl. Med. 2010; 51:1584-1591.
80. Guillin, O, Abi-Dargham, A, and Laruelle, M. Neurobiology of dopamine in schizophrenia. Int. Review Neurobiol. 2007; 78: 1-39.
81. Jentsch, JD and Roth, RH. The neuropsychopharmacology of phencyclidine: From NMDA receptor hypofunction to the dopamine hypothesis of schizophrenia. Neuropsychopharmacol. 1999; 20:201-225.
82. Menniti FS, Chappie TA, Humphrey JM et al.: Phosphodiesterase 10A inhibitors: A novel approach to the treatment of the symptoms of schizophrenia. Curr Opin Invest Drugs 2007; 8(1):54-59.
83. Chappie T, Humphrey J, Menniti F et al.: PDE10A inhibitors: An assessment of the current CNS drug discovery landscape Current Opinion in Drug Discovery & Development 2009; 12(4):458-467.
84. Wadenberg MLG, Hicks PB: The conditioned avoidance response test re-evaluated: Is it a sensitive test for the detection of potentially atypical antipsychotics? Neurosci. Biobehav. Rev.1999; 23(6):851-862.
85. Kapur S. Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia. Am. J. Psychiatry 2003; 160(1):13-23.
86. Hoffman D, Donovan H: 28. Catalepsy as a rodent model for detecting antipsychotic drugs with extrapyramidal side effect liability. Psychopharmacology 1995; 120(2):128-133.
87. Kapur S, Zipursky R, Jones C, Remington G, Houle S. Relationship Between Dopamine D2 Occupancy, Clinical Response, and Side Effects: A Double-Blind PET Study of First-Episode Schizophrenia Am. J. Psychiatry 2000: 157: 514-520.
88. Marquis KL, Sabb AL, Logue SF, Brennan JA, Piesla MJ, Comery TA, Grauer SM, Ashby CR Jr., Nguyen HQ, Dawson LA, et al. (2007) WAY-163909 [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepin o[6,7,1hi]indole]: A novel5-hydroxytryptamine 2C receptor-selective agonist with preclinical antipsychotic-like activity. J Pharmacol Exp Ther 320:486-496.
89. Rodefer JS, Murphy ER, and Baxter MG. PDE10A inhibition reverses subchronic PCP-induced deficits in attentional set-shifting in rats. Eur J Neurosci 2005; 21:1070-1076.
90. Bergmann JE, Cutshall NS, Onrust R, Zeng H, Gage JL, Johnston D, Cseh S, Urogdi L, Papp A. PDE10 inhibitors and related compositions and methods. US-20080300240; Omeros Corp. 2008.
91. Arrington MP, Liu R, Hopper AT, Conticello RD, Nguyen TM, Gauss CM, Burli R, Hitchcock SA, Hu E, Kunz R, Nixey T et al. Cinnoline derivatives as phosphodiesterase 10 inhibitors. WO-2007098169. Amgen Inc/Memory Pharmaceuticals Corp. 2007.
92. Braff DL, Light GA. Preattentional and attentional cognitive deficits as targets for treating schizophrenia. Psychopharmacology 2004; 174(1):75-85.
93. Geyer M, Krebs-Thomson K, Braff D, Swerdlow N: Pharmacological studies of prepulse inhibition models of sensorimotor gating deficits in schizophrenia: A decade in review. Psychopharmacology 2001; 156(2-3):117-154.
94. Hajós M. Targeting information-processing deficit in schizophrenia: A novel approach to sychotherapeutic drug discovery. Trends Pharmacol. Sci. 2006; 27(7):391-398.
95. Sano H, Nagai Y, Miyakawa T, Shigemoto R, and Yokoi M. Increased social interaction in mice deficient of the striatal medium spiny neuron-specific phosphodiesterase 10A2. J Neurochem 2008; 105:546-556.
96. Threlfell S, Sammut S, Menniti FS, Schmidt CJ, West AR: 29. Inhibition of phosphodiesterase 10A increases the responsiveness of striatal projection neurons to cortical stimulation. J. Pharmacol. Exp. Ther. 2009; 328(3):785-795.
97. Kucka M, Kretschmannova K, Murano T, Wu CP, Zemkova H, Ambudkar SV, Stojilkovic SS. Dependence of Multidrug Resistance Protein-Mediated Cyclic Nucleotide Efflux on the Background Sodium Conductance. Mol. Pharmacol. 2010; 77:270-279.
98. Surmeier DJ, Day M, Gertler T, Chan S, Shen W. D1 and D2 Dopamine Receptor Modulation of Glutamatergic Signaling in Striatal Medium Spiny Neurons. Handbook of Behavioral Neuroscience 2010; 20: 113-133.
99. For recent patent reviews relating to PDE10A inhibitors see ref 68 and: a) Kehler J, Kilburn J. Patented PDE10A inhibitors: novel compounds since 2007. Expert Opinion on Therapeutic Patents. 2009, 19(12): 1715-1725.
100. Kehler J, Ritzen A, Greve DR. The potential therapeutic use of phosphodiesterase 10 inhibitors. Expert Opinion on Therapeutic Patents. 2007; 17(2): 147-158.
101. Niewoehner U, Bauser M, Ergueden J-K, Flubacher D, Naab P, Repp T-O, Stoltefuss J, Burkhardt N, Sewing A, Schauer M, Schlemmer K-H, Weber O, Boyer S, Miglarese M. Preparation of pyrrolo[2,1-a]isoquinolines as phosphodiesterase 10a inhibitors. 2002, WO2002048144; CAN 137:47106. Bayer Aktiengesellschaft.
102. Lebel LA, Menniti FS, Schmidt CJ. Use of selective phosphodiesterase-10 inhibitors for the treatment of central nervous system disorders. 2002, EP1250923, CAN 137:289036, Pfizer.
103. Nagasawa M, MacKenzie SJ. Ibudilast is a potent phosphodiesterase 10A inhibitor useful in treatment of neurological disorders. 2004, WO2004050091, CAN 141:35467, Kyorin Pharmaceutical Co., Ltd.
104. Osakada N, Haruoka M, Ikeda K, Toki S, Miyaji H, Shimada J. Preparation of quinoline derivatives as phosphodiesterase 10A inhibitors. 2004, WO2004002484, CAN 140:77039; Kyowa Hakko Kogyo Co., Ltd.
105. Maier T, Graedler U, Baer T, Vennemann M. Pyrrolodihydroisoquinoline derivatives as PDE10 inhibitors. 2005, WO2005002579, CAN 142:134478, Altana Pharma A.-G.
106. Arrington MP, Liu R, Conticello RD, Gauss CM, Hopper A, Nguyen TM, Tehim A. Preparation of 4,6-dialkoxy-cinnoline derivatives as phosphodiesterase 10 inhibitors for the treatment of psychiatric or neurological syndromes. 2006, WO2006028957, CAN 144:292767, Memory Pharmaceuticals Corporation.
107. Robertson HA, Denovan-Wright EM, Weaver D. Benzofuran-ylpyridone and indole compounds for modulating phosphodiesterase 10A. 2007, US2007060606, CAN 146:311484, Dalhousie University, Can.
108. Nielsen EB, Kehler J, Nielsen J, Broesen P. Use of tofisopam as a PDE10a inhibitor. 2007, WO2007082546, CAN 147:181558, H. Lundbeck A/S.
109. Hoefgen N, Stange H, Langen B, Egerland U, Schindler R, Pfeifer T, Rundfeldt C. Preparation of imidazo[1,5-a]pyrido[3,2-e]pyrazines as inhibitors of phosphodiesterase10.2007, WO2007137820, CAN 148:33771, Elbion A.-G.
110. Cutshall NS, Johnston D, Urogdi L, Bergmann JE, Onrust R, Hongkui Z, Cseh S, Papp A. Preparation of heterocyclyl ben-zylideneacetohydrazides as phosphodiesterase PDE10 inhibitors. 2008, WO2008064342, CAN 149:10025, Omeros Corporation.
111. Ripka A, Shapiro G, Chesworth R. 5- And 6-membered heterocyclic compounds as phosphodiesterase inhibitors and their preparation, pharmaceutical compositions and use in the treatment of CNS disorders and disorders affected by CNS function. 2009, WO2009158473, CAN 152:97510, Envivo Pharmaceuticals, Inc.
112. Kawanishi E, Matsumura T. Preparation of trisubstituted pyrimidines as phosphodiesterase PDE10 inhibitors. 2010, WO2010027097, CAN 152:335232, Mitsubishi Tanabe Pharma Corporation.
113. Ho GD, Yang S-W, Smith EM, Mcelroy WT, Basu K, Smotryski J, Tan Z, McKittrick BA, Tulshian DB. Preparation of substituted pyrazoloquinolines and derivatives thereof. 2010, WO2010062559, CAN 153:37159, Schering Corporation.
114. Alberati D, Gobbi L, Koerner M, Kuhn B, Peters J-U, Rodriguez Sarmiento RM, Rogers-Evans M, Rudolph M. Preparation of pyridazinone derivatives as PDE10A inhibitors.2010, WO2010063610, CAN 153:37177, F. Hoffmann-La Roche AG.
115. Taniguchi T, Kawada A, Kondo M, Quinn JF, Kunitomo J, Yoshikawa M, Fushimi M. Preparation of pyridazinone compounds as phosphodiesterase 10A inhibitors for preventing and treating schizophrenia. 2010, US2010197651, CAN 153:287025, Takeda Pharmaceutical Company Limited.
116. Andres-Gil JI, Bormans GMR, De Angelis M, Celen SJL. Radiolabelled PDE10 ligands. 2010, WO2010097367, CAN 153:353007, Janssen Pharmaceutica NV.
117. Johansson P. Astra Zeneca. Fragment-assisted lead generation in PDE10; a synergistic combination of FBLG & HTS to accelerate hit identification. 18th annual meeting for structural biologists working in the pharmaceutical industry; 15th nov. PSDI 2010.
118. Albert J. Astra Zeneca. Fragment assisted lead generation: Discovery of new high-affinity PDE10 inhibitors. Structural Biology and Drug Discovery Conference 4-7th dec. 2010, Puerto Morelos, Mexico.
119. Albrecht C, Fryatt T, Andersen O, Felicetti B, Ellenbroek B, Kahrs A, Scholz P, Rahlff J, Prahm M, Schonfeld D, Toogood-Johnson I, Winkler D, Kahmann J, Raoof A, Meniconi M, Pal S, Bentley J, Barker J, Hesterkamp T, Gemkow M, Hallett D, Kemp J, Moraes I. Identification of fragment inhibitors of phosphodiesterase 10a (PDE10a). 2010, Keystone Symposia in Small Molecule Drug Discovery, 20-25 Apr, Whistler, Canada.
120. Loughney K. Protein and cDNA sequences of human phosphodiesterase 10 (PDE10). 1999, WO9942596, CAN 131:166238, Icos Corporation.
121. no reference in tex, so reference non-existing.
122. Gerfen CR, Bolam JP. The Neuroanatomical Organization of the Basal Ganglia. Handbook of Behavioral Neuroscience 2010; 20: 3-28.
123. Dreyer JK, Herrik KF, Berg RW, Hounsgaard JD. Influence of Phasic and Tonic Dopamine Release on Receptor Activation. J. Neurosci. 2010; 30(42):14273-14283.
124. Uthayathas S, Masilamoni JG, Menniti FS, Schmidt CJ, Smith Y, Wichmann T, Papa SM. Effects of Inhibition of Phosphodiesterase 10A on Motor Behavior and Brain Metabolic Activity in Monkeys. SfN 2010 Annual Meeting, November 2010, San Diego. Poster 491.21.
125. Sotty F, Montezinho LP, Steiniger-Brach B, Nielsen J. Phosphodiesterase 10A inhibition modulates the sensitivity of the mesolimbic dopaminergic system to d-amphetamine: involvement of the D1-regulated feedback control of midbrain dopamine neurons. J. Neurochem. 2009; 109:766-775.