Schizophrenia drug discovery and development in an evolving era: Are new drug targets fulfilling expectations?

Journal of Psychopharmacology

Volumn 29, Issue 2, 2015, Pages 230-238

  Dunlop, John ^a   Brandon, Nicholas J ^a  

^a ASTRAZENECA   (United Kingdom)

Author keywords

drug discovery; new targets; Schizophrenia

Indexed keywords

2 [4 [1 METHYL 4 (4 PYRIDINYL) 3 PYRAZOLYL]PHENOXYMETHYL]QUINOLINE; 3 [3 [(2,4 DIMETHOXYPHENYL)METHYLIDENE] 5,6 DIHYDRO 4H PYRIDIN 2 YL]PYRIDINE; 4 AMINO 2 THIABICYCLO[3.1.0]HEXANE 4,6 DICARBOXYLIC ACID 2,2 DIOXIDE; ADX 71149; AZD 8529; BITOPERTIN; BUNGAROTOXIN RECEPTOR; ENCENICLINE; GLYCINE TRANSPORTER; JNJ 42314415; METABOTROPIC RECEPTOR 2; METABOTROPIC RECEPTOR 3; NEUROLEPTIC AGENT; OLANZAPINE; PLACEBO; POMAGLUMETAD METHIONIL; RISPERIDONE; RO 5545965; UNCLASSIFIED DRUG; GLUTAMATE RECEPTOR; PHOSPHODIESTERASE;

ARTICLE; BODY WEIGHT DISORDER; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG STRUCTURE; DRUG TOLERABILITY; DRUG TREATMENT FAILURE; EXTRAPYRAMIDAL SYMPTOM; HUMAN; HUNTINGTON CHOREA; MIXED ANXIETY AND DEPRESSION; MONOTHERAPY; NONHUMAN; POSITIVE AND NEGATIVE SYNDROME SCALE; PROTEIN EXPRESSION; PROTEIN FUNCTION; SCHIZOPHRENIA; SIGNAL TRANSDUCTION; TREATMENT DURATION; TREATMENT RESPONSE; ANIMAL; DRUG DELIVERY SYSTEM; DRUG DEVELOPMENT; METABOLISM; PROCEDURES;

ALPHA7 NICOTINIC ACETYLCHOLINE RECEPTOR; ANIMALS; ANTIPSYCHOTIC AGENTS; DRUG DELIVERY SYSTEMS; DRUG DISCOVERY; GLYCINE PLASMA MEMBRANE TRANSPORT PROTEINS; HUMANS; PHOSPHORIC DIESTER HYDROLASES; RECEPTORS, GLUTAMATE; SCHIZOPHRENIA;

EID: 84922219054     PISSN: 02698811     EISSN: 14617285     Source Type: Journal    
DOI: 10.1177/0269881114565806     Document Type: Article

References (72)

1. Adams DH, Kinon BJ, Baygani S, et al. A long-term, phase 2, multicenter, randomized, open-label, comparative safety study of pomaglumetad methionil (LY2140023 monohydrate) versus atypical antipsychotic standard of care in patients with schizophrenia. BMC Psychiatry. 2013 ; 13: 143
2. Ahmad R, Bourgeois S, Postnov A, et al. PET imaging shows loss of striatal PDE10A in patients with Huntington disease. Neurology. 2014 ; 82: 279-281
3. Alberati D, Moreau JL, Lengyel J, et al. Glycine reuptake inhibitor RG1678: A pharmacologic characterization of an investigational agent for the treatment of schizophrenia. Neuropharmacology. 2012 ; 62: 1152-1161
4. Barret O, Thomae D, Tavares A, et al. In vivo assessment and dosimetry of 2 novel PDE10A PET radiotracers in humans: 18F-MNI-659 and 18F-MNI-654. J Nucl Med. 2014 ; 55: 1297-1304
5. Bergeron R, Meyer TM, Coyle JT, et al. Modulation of N-methyl-D-aspartate receptor function by glycine transport. Proc Natl Acad Sci U S A. 1998 ; 95: 15730-15734
6. Bleickardt CJ, Kazdoba TM, Jones NT, et al. Antagonism of the adenosine A2A receptor attenuates akathisia-like behavior induced with MP-10 or aripiprazole in a novel non-human primate model. Pharmacol Biochem Behav. 2014 ; 118: 36-45
7. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): The efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007 ; 164: 1593-1602
8. Charych EI, Brandon NJ In Cyclic-Nucleotide Phosphodiesterases in the Central Nervous System. Brandon NJ, ed. Hoboken, NJ: John Wiley & Sons, Inc. ; 2014: 247-268.
9. Cook D, Brown D, Alexander R, et al. Lessons learned from the fate of AstraZeneca's drug pipeline: A five-dimensional framework. Nat Rev Drug Discov. 2014 ; 13: 419-431
10. Coskran TM, Morton D, Menniti FS, et al. Immunohistochemical localization of phosphodiesterase 10A in multiple mammalian species. J Histochem Cytochem. 2006 ; 54: 1205-1213
11. Dani JA, Bertrand D. Nicotinic acetylcholine receptors and nicotinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol. 2007 ; 47: 699-729
12. DeMartinis NBA, Kumar V, Boyer S, et al. Results of a phase 2A proof-of-concept trial with a PDE10A inhibitor in the treatment of acute exacerbation of schizophrenia. Schizophrenia Research. 2012 ; 136: S212
13. Demjaha A, Egerton A, Murray RM, et al. Antipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function. Biol Psychiatry. 2014 ; 75: e11 - e13
14. Dunlop J, Brandon NJ. The road ahead - a perspective of drug discovery in psychiatry in 2013 from inside an evolving industry. The Biochemist. 2013 ; 35: 24-29
15. Evins AE, Amico E, Posever TA, et al. D-cycloserine added to risperidone in patients with primary negative symptoms of schizophrenia. Schizophr Res. 2002 ; 56: 19-23
16. Fell MJ, McKinzie DL, Monn JA, et al. Group II metabotropic glutamate receptor agonists and positive allosteric modulators as novel treatments for schizophrenia. Neuropharmacology. 2012 ; 62: 1473-1483
17. Fell MJ, Svensson KA, Johnson BG, et al. Evidence for the role of metabotropic glutamate (mGlu)2 not mGlu3 receptors in the preclinical antipsychotic pharmacology of the mGlu2/3 receptor agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther. 2008 ; 326: 209-217
18. Fromer M, Pocklington AJ, Kavanagh DH, et al. De novo mutations in schizophrenia implicate synaptic networks. Nature. 2014 ; 506: 179-184
19. Goff DC, Tsai G, Manoach DS, et al. D-cycloserine added to clozapine for patients with schizophrenia. Am J Psychiatry. 1996 ; 153: 1628-1630
20. Gonzalez-Burgos G, Lewis DA. NMDA receptor hypofunction, parvalbumin-positive neurons, and cortical gamma oscillations in schizophrenia. Schizophr Bull. 2012 ; 38: 950-957
21. Grauer SM, Pulito VL, Navarra RL, et al. Phosphodiesterase 10A inhibitor activity in preclinical models of the positive, cognitive, and negative symptoms of schizophrenia. J Pharmacol Exp Ther. 2009 ; 331: 574-590
22. Hajos M, Rogers BN. Targeting alpha7 nicotinic acetylcholine receptors in the treatment of schizophrenia. Curr Pharm Des. 2010 ; 16: 538-554
23. Haydar SN, Dunlop J. Neuronal nicotinic acetylcholine receptors - targets for the development of drugs to treat cognitive impairment associated with schizophrenia and Alzheimer's disease. Curr Top Med Chem. 2010 ; 10: 144-152
24. Heresco-Levy U, Javitt DC, Ermilov M, et al. Double-blind, placebo-controlled, crossover trial of glycine adjuvant therapy for treatment-resistant schizophrenia. Br J Psychiatry. 1996 ; 169: 610-617
25. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: Version III-the final common pathway. Schizophr Bull. 2009 ; 35: 549-562
26. Javitt DC. Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol. 2012 ;: 367-399
27. Javitt DC, Zylberman I, Zukin SR, et al. Amelioration of negative symptoms in schizophrenia by glycine. Am J Psychiatry. 1994 ; 151: 1234-1236
28. Kehler J. Phosphodiesterase 10A inhibitors: A 2009-2012 patent update. Expert Opin Ther Pat. 2013 ; 23: 31-45
29. Kehler J, Nielsen J. PDE10A inhibitors: Novel therapeutic drugs for schizophrenia. Curr Pharm Des. 2011 ; 17: 137-150
30. Kinon BJ. The development of pomaglumetad methionil as an innovative glutamate-based pharmacotherapy for schizophrenia. Neuropsychopharmacology. 2013 ; 38: S1 - S107
31. Kinon BJ, Zhang L, Millen BA, et al. A multicenter, inpatient, phase 2, double-blind, placebo-controlled dose-ranging study of LY2140023 monohydrate in patients with DSM-IV schizophrenia. J Clin Psychopharmacol. 2011 ; 31: 349-355
32. Krystal JH, Mathew SJ, D'Souza DC, et al. Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs. 2010 ; 24: 669-693
33. Kurita M, Holloway T, Garcia-Bea A, et al. HDAC2 regulates atypical antipsychotic responses through the modulation of mGlu2 promoter activity. Nat Neurosci. 2012 ; 15: 1245-1254
34. Kurita M, Moreno JL, Holloway T, et al. Repressive epigenetic changes at the mGlu2 promoter in frontal cortex of 5-HT2A knockout mice. Mol Pharmacol. 2013 ; 83: 1166-1175
35. Lavreysen H. Discovery and Early Clinical development of novel mGlu2 receptor PAMs. Neuropsychopharmacology. 2013 ; 38: S1 - S107
36. Levin ED, McClernon FJ, Rezvani AH. Nicotinic effects on cognitive function: Behavioral characterization, pharmacological specification, and anatomic localization. Psychopharmacology (Berl). 2006 ; 184: 523-539
37. Liu W, Downing AC, Munsie LM, et al. Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia. Pharmacogenomics J. 2012 ; 12: 246-254
38. McNally JM, McCarley RW, Brown RE. Impaired GABAergic neurotransmission in schizophrenia underlies impairments in cortical gamma band oscillations. Curr Psychiatry Rep. 2013 ; 15: 346-361
39. Marsman A, van den Heuvel MP, Klomp DW, et al. Glutamate in schizophrenia: A focused review and meta-analysis of (1)H-MRS studies. Schizophr Bull. 2013 ; 39: 120-129
40. Martin LF, Freedman R. Schizophrenia and the alpha7 nicotinic acetylcholine receptor. Int Rev Neurobiol. 2007 ; 78: 225-246
41. Martin-Facklam M, Pizzagalli F, Zhou Y, et al. Glycine transporter type 1 occupancy by bitopertin: A positron emission tomography study in healthy volunteers. Neuropsychopharmacology. 2013 ; 38: 504-512
42. Maurice DH, Ke H, Ahmad F, et al. Advances in targeting cyclic nucleotide phosphodiesterases. Nat Rev Drug Discov. 2014 ; 13: 290-314
43. Megens AA, Hendrickx HM, Hens KA, et al. Pharmacology of JNJ-42314415, a centrally active phosphodiesterase 10A (PDE10A) inhibitor: A comparison of PDE10A inhibitors with D2 receptor blockers as potential antipsychotic drugs. J Pharmacol Exp Ther. 2014 ; 349: 138-154
44. Meltzer HY. Update on typical and atypical antipsychotic drugs. Annu Rev Med. 2013 ; 64: 393-406
45. Moghaddam B, Krystal JH. Capturing the angel in 'angel dust': Twenty years of translational neuroscience studies of NMDA receptor antagonists in animals and humans. Schizophr Bull. 2012 ; 38: 942-949
46. Mothet JP, Parent AT, Wolosker H, et al. D-serine is an endogenous ligand for the glycine site of the N-methyl-D-aspartate receptor. Proc Natl Acad Sci U S A. 2000 ; 97: 4926-4931
47. Nestler EJ, Hyman SE. Animal models of neuropsychiatric disorders. Nat Neurosci. 2010 ; 13: 1161-1169
48. Olincy A, Harris JG, Johnson LL, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry. 2006 ; 63: 630-638
49. Papouin T, Ladepeche L, Ruel J, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell. 2012 ; 150: 633-646
50. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: A randomized Phase 2 clinical trial. Nat Med. 2007 ; 13: 1102-1107
51. Plisson C, Weinzimmer D, Jakobsen S, et al. Phosphodiesterase 10A PET radioligand development program: From pig to human. J Nucl Med. 2014 ; 55: 595-601
52. Preskorn SH, Gawryl M, Dgetluck N, et al. Normalizing effects of EVP-6124, an alpha-7 nicotinic partial agonist, on event-related potentials and cognition: A proof of concept, randomized trial in patients with schizophrenia. J Psychiatr Pract. 2014 ; 20: 12-24
53. Prickaerts J, van Goethem NP, Chesworth R, et al. EVP-6124, a novel and selective alpha7 nicotinic acetylcholine receptor partial agonist, improves memory performance by potentiating the acetylcholine response of alpha7 nicotinic acetylcholine receptors. Neuropharmacology. 2012 ; 62: 1099-1110
54. Purcell SM, Moran JL, Fromer M, et al. A polygenic burden of rare disruptive mutations in schizophrenia. Nature. 2014 ; 506: 185-190
55. Rizzo SJ, Edgerton JR, Hughes ZA, et al. Future viable models of psychiatry drug discovery in pharma. J Biomol Screen. 2013 ; 18: 509-521
56. Rorick-Kehn LM, Johnson BG, Burkey JL, et al. Pharmacological and pharmacokinetic properties of a structurally novel, potent, and selective metabotropic glutamate 2/3 receptor agonist: In vitro characterization of agonist (-)-(1R,4S,5S,6S)-4-amino-2-sulfonylbicyclo[3.1.0]-hexane-4,6-dicarboxylic acid (LY404039). J Pharmacol Exp Ther. 2007 ; 321: 308-317
57. Rosenzweig-Lipson S, Comery TA, Marquis KL, et al. 5-HT(2C) agonists as therapeutics for the treatment of schizophrenia. Handb Exp Pharmacol. 2012 ; 213: 147-165
58. Russell DS, Barret O, Jennings DL, et al. The phosphodiesterase 10 positron emission tomography tracer, [18F]MNI-659, as a novel biomarker for early Huntington disease. JAMA Neurol. 2014 ; 71: 1520-1528
59. Rutter AR, Fradley RL, Garrett EM, et al. Evidence from gene knockout studies implicates Asc-1 as the primary transporter mediating d-serine reuptake in the mouse CNS. Eur J Neurosci. 2007 ; 25: 1757-1766
60. Biological insights from 108 schizophrenia-associated genetic loci. Nature. 2014 ; 511: 421-427
61. Schmidt CJ, Chapin DS, Cianfrogna J, et al. Preclinical characterization of selective phosphodiesterase 10A inhibitors: A new therapeutic approach to the treatment of schizophrenia. J Pharmacol Exp Ther. 2008 ; 325: 681-690
62. Smith A, Li M, Becker S, et al. A model of antipsychotic action in conditioned avoidance: A computational approach. Neuropsychopharmacology. 2004 ; 29: 1040-1049
63. Smith SM, Uslaner JM, Cox CD, et al. The novel phosphodiesterase 10A inhibitor THPP-1 has antipsychotic-like effects in rat and improves cognition in rat and rhesus monkey. Neuropharmacology. 2013 ; 64: 215-223
64. Stauffer VL, Millen BA, Andersen S, et al. Pomaglumetad methionil: No significant difference as an adjunctive treatment for patients with prominent negative symptoms of schizophrenia compared to placebo. Schizophr Res. 2013 ; 150: 434-441
65. Tsai G, Yang P, Chung LC, et al. D-serine added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry. 1998 ; 44: 1081-1089
66. Umbricht D, Alberati D, Martin-Facklam M, et al. Effect of bitopertin, a glycine reuptake inhibitor, on negative symptoms of schizophrenia: A randomized, double-blind, proof-of-concept study. JAMA Psychiatry. 2014 ; 71: 637-646
67. Uthayathas S, Masilamoni GJ, Shaffer CL, et al. Phosphodiesterase 10A inhibitor MP-10 effects in primates: Comparison with risperidone and mechanistic implications. Neuropharmacology. 2014 ; 77: 257-267
68. Verrall L, Burnet PW, Betts JF, et al. The neurobiology of D-amino acid oxidase and its involvement in schizophrenia. Mol Psychiatry. 2010 ; 15: 122-137
69. Verrall L, Walker M, Rawlings N, et al. d-Amino acid oxidase and serine racemase in human brain: Normal distribution and altered expression in schizophrenia. Eur J Neurosci. 2007 ; 26: 1657-1669
70. Wadenberg ML, 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: 851-862
71. Weiser M, Heresco-Levy U, Davidson M, et al. A multicenter, add-on randomized controlled trial of low-dose d-serine for negative and cognitive symptoms of schizophrenia. J Clin Psychiatry. 2012 ; 73: e728 - e734
72. Wilson LS, Brandon NJ. Emerging biology of PDE10A. Curr Pharm Des. 2014 ; 21: 378-388