The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold
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- 作者：Anthony L Gotter (1)
Christopher J Winrow (1)
Joseph Brunner (1)
Susan L Garson (1)
Steven V Fox (2)
Jacquelyn Binns (2)
Charles M Harrell (1)
Donghui Cui (3)
Ka Lai Yee (3)
Mark Stiteler (2)
Joanne Stevens (2)
Alan Savitz (2)
Pamela L Tannenbaum (2)
Spencer J Tye (2)
Terrence McDonald (1)
Leon Yao (2)
Scott D Kuduk (4)
Jason Uslaner (2)
Paul J Coleman (4)
John J Renger (1) - 关键词：Dual orexin receptor antagonist ; Suvorexant ; Receptor occupancy ; Residual effects
- 刊名：BMC Neuroscience
- 出版年：2013
- 出版时间：December 2013
- 年：2013
- 卷：14
- 期：1
- 全文大小：790KB
- 参考文献：1. Espana RA, Scammell TE: Sleep neurobiology from a clinical perspective. / Sleep 2011, 34:845-58.
2. Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ: International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology. / Pharmacol Rev 2012, 64:389-20. CrossRef
3. Taheri S, Sunter D, Dakin C, Moyes S, Seal L, Gardiner J, Rossi M, Ghatei M, Bloom S: Diurnal variation in orexin A immunoreactivity and prepro-orexin mRNA in the rat central nervous system. / Neurosci Lett 2000, 279:109-12. CrossRef
4. Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E: Circadian and homeostatic regulation of hypocretin in a primate model: Implications for the consolidation of wakefulness. / J Neurosci 2003, 23:3555-560.
5. De Lecea L, Kilduff TS, Peyron C, Gao XB, Foye PE, Danielson PE, Fukuhara C, Battenberg ELF, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG: The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity. / Proc Natl Acad Sci U S A 1998, 95:322-27. CrossRef
6. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JRS, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M: Orexins and orexin receptors: A family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. / Cell 1998, 92:573-85. CrossRef
7. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, Benham CD, Taylor SG, Routledge C, Hemmati P, Munton RP, Ashmeade TE, Shah AS, Hatcher JP, Hatcher PD, Jones DNC, Smith MI, Piper DC, Hunter AJ, Porter RA, Upton N: Orexin A activates locus coeruleus cell firing and increases arousal in the rat. / Proc Natl Acad Sci U S A 1999, 96:10911-0916. CrossRef
8. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M: Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. / Proc Natl Acad Sci U S A 2004, 101:4649-654. CrossRef
9. Piper DC, Upton N, Smith MI, Hunter AJ: The novel brain neuropeptide, orexin-A, modulates the sleep-wake cycle of rats. / Eur J Neurosci 2000, 12:726-30. CrossRef
10. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, Van Gerven J, De Haas SL, Hess P, Qiu CB, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F: Promotion of sleep by targeting the orexin system in rats, dogs and humans. / Nat Med 2007, 13:150-55. CrossRef
11. Li AH, Nattie E: Antagonism of rat orexin receptors by almorexant attenuates central chemoreception in wakefulness in the active period of the diurnal cycle. / J Physiol 2010, 588:2935-944. CrossRef
12. Winrow CJ, Gotter AL, Cox CD, Doran SM, Tannenbaum PL, Breslin MJ, Garson SL, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ: Promotion of sleep by suvorexant - a novel dual orexin receptor antagonist. / J Neurogenet 2011, 25:52-1. CrossRef
13. Roehrs T, Roth T: Insomnia pharmacotherapy. / Neurotherapeutics 2012, 9:728-38. CrossRef
14. Roth T: A physiologic basis for the evolution of pharmacotherapy for insomnia. / J Clin Psychiatry 2007,68(Suppl 5):13-8.
15. Bettica P, Squassante L, Groeger JA, Gennery B, Winsky-Sommerer R, Dijk DJ: Differential effects of a dual orexin receptor antagonist (SB-649868) and zolpidem on sleep initiation and consolidation, SWS, REM sleep, and EEG power spectra in a model of situational insomnia. / Neuropsychopharmacology 2012, 37:1224-233. CrossRef
16. Di Fabio R, Pellacani A, Faedo S, Roth A, Piccoli L, Gerrard P, Porter RA, Johnson CN, Thewlis K, Donati D, Stasi L, Spada S, Stemp G, Nash D, Branch C, Kindon L, Massagrande M, Poffe A, Braggio S, Chiarparin E, Marchioro C, Ratti E, Corsi M: Discovery process and pharmacological characterization of a novel dual orexin 1 and orexin 2 receptor antagonist useful for treatment of sleep disorders. / Bioorg Med Chem Lett 2011, 21:5562-567. CrossRef
17. Herring WJ, Snyder E, Budd K, Hutzelmann J, Snavely D, Liu K, Lines C, Roth T, Michelson D: Orexin receptor antagonism for treatment of insomnia: A randomized clinical trial of suvorexant. / Neurology 2012, 79:2265-274. CrossRef
18. Winrow CJ, Gotter AL, Cox CD, Tannenbaum PL, Garson SL, Doran SM, Breslin MJ, Schreier JD, Fox SV, Harrell CM, Stevens J, Reiss DR, Cui D, Coleman PJ, Renger JJ: Pharmacological characterization of MK-6096 - a dual orexin receptor antagonist for insomnia. / Neuropharmacology 2012, 62:978-87. CrossRef
19. Coleman PJ, Schreier JD, Cox CD, Breslin MJ, Whitman DB, Bogusky MJ, McGaughey GB, Bednar RA, Lemaire W, Doran SM, Fox SV, Garson SL, Gotter AL, Harrell CM, Reiss DR, Cabalu TD, Cui D, Prueksaritanont T, Stevens J, Tannenbaum PL, Ball RG, Stellabott J, Young SD, Hartman GD, Winrow CJ, Renger JJ: Discovery of [(2R,5R)-5-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-methylpiperidin-1-yl][5-methyl-2 -(pyrimidin-2-yl)phenyl]methanone (MK-6096): a dual orexin receptor antagonist with potent sleep-promoting properties. / ChemMedChem 2012, 7:415-4. 337 CrossRef
20. Fox SV, Gotter AL, Tye SJ, Garson SL, Savitz AT, Uslaner JM, Brunner JI, Tannenbaum PL, McDonald TP, Hodgson R, Yao L, Bowlby MR, Kuduk SD, Coleman PJ, Hargreaves R, Winrow CJ, Renger JJ: Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats. / Neuropsychopharmacology 2013. doi:10.1038/npp.2013.139
21. Cox CD, Breslin MJ, Whitman DB, Schreier JD, McGaughey GB, Bogusky MJ, Roecker AJ, Mercer SP, Bednar RA, Lemaire W, Bruno JG, Reiss DR, Harrell CM, Murphy KL, Garson SL, Doran SM, Prueksaritanont T, Anderson WB, Tang C, Roller S, Cabalu TD, Cui D, Hartman GD, Young SD, Koblan KS, Winrow CJ, Renger JJ, Coleman PJ: Discovery of the dual orexin receptor antagonist [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methy l-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the treatment of insomnia. / J Med Chem 2010, 53:5320-332. CrossRef
22. Gotter AL, Roecker AJ, Hargreaves R, Coleman PJ, Winrow CJ, Renger JJ: Orexin receptors as therapeutic drug targets. / Prog Brain Res 2012, 198:163-8. CrossRef
23. Faedo S, Perdona E, Antolini M, Di FR, Merlo PE, Corsi M: Functional and binding kinetic studies make a distinction between OX1 and OX2 orexin receptor antagonists. / Eur J Pharmacol 2012, 692:1-. CrossRef
24. Uslaner JM, Tye SJ, Eddins DM, Wang X, Fox SV, Savitz AT, Binns J, Cannon CE, Garson SL, Yao L, Hodgson R, Stevens J, Bowlby MR, Tannenbaum PL, Brunner J, McDonald TP, Gotter AL, Kuduk SD, Coleman PJ, Winrow CJ, Renger JJ: Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. / Sci Transl Med 2013, 5:179ra44. CrossRef
25. Abadie P, Rioux P, Scatton B, Zarifian E, Barre L, Patat A, Baron JC: Central benzodiazepine receptor occupancy by zolpidem in the human brain as assessed by positron emission tomography. / Eur J Pharmacol 1996, 295:35-4. CrossRef
26. Martins PJ, D’Almeida V, Pedrazzoli M, Lin L, Mignot E, Tufik S: Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity. / Regul Pept 2004, 117:155-. CrossRef
27. Allen RP, Mignot E, Ripley B, Nishino S, Earley CJ: Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome. / Neurology 2002, 59:639-1. CrossRef
28. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E: Hypocretin (orexin) deficiency in human narcolepsy. / Lancet 2000, 355:39-0. CrossRef
29. Dugovic C, Shelton JE, Aluisio LE, Fraser IC, Jiang XH, Sutton SW, Bonaventure P, Yun SJ, Li XR, Lord B, Dvorak CA, Carruthers NI, Lovenberg TW: Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat. / J Pharmacol Exp Ther 2009, 330:142-51. CrossRef
30. Morairty SR, Revel FG, Malherbe P, Moreau JL, Valladao D, Wettstein JG, Kilduff TS, Borroni E: Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. / PLoS One 2012, 7:e39131. CrossRef
31. Farde L, Nordstr?m AL, Wiesel FA, Pauli S, Halldin C, Sedvall G: Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. / Relation to extrapyramidal side effects. Arch Gen Psychiatry 1992, 49:538-4. CrossRef
32. Wong DF, Tauscher J, Gründer G: The role of imaging in proof of concept for CNS drug discovery and development. / Neuropsychopharmacology 2009, 34:187-03. CrossRef
33. Dijk DJ, James LM, Peters S, Walsh JK, Deacon S: Sex differences and the effect of gaboxadol and zolpidem on EEG power spectra in NREM and REM sleep. / J Psychopharmacol 2010, 24:1613-618. CrossRef
34. Walsh JK, Deacon S, Dijk DJ, Lundahl J: The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. / Sleep 2007, 30:593-02.
35. Steiner MA, Lecourt H, Strasser DS, Brisbare-Roch C, Jenck F: Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-alpha1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. / Neuropsychopharmacology 2011, 36:848-56. CrossRef
36. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin XY, Qiu XH, De Jong PJ, Nishino S, Mignot E: The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. / Cell 1999, 98:365-76. CrossRef
37. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong YM, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M: Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation. / Cell 1999, 98:437-51. CrossRef
38. Willie JT, Chemelli RM, Sinston CM, Tokita H, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA, Leonard CS, Richardson JA, Hammer RE, Yanagisawa M: Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: Molecular genetic dissection of non-REM and REM sleep regulatory processes. / Neuron 2003, 38:715-30. CrossRef
39. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M: To eat or to sleep? Orexin in the regulation of feeding and wakefulness. / Annu Rev Neurosci 2001, 24:429-58. CrossRef
40. Sun H, Kennedy D, Lewis N, Laethem T, Yee K, Li X, Hoon J, Van Bortel L, Rosen L, Chodakewitz J, Wagner JA, Murphy MG: The single dose pharmacokinetic (PK) and pharmacodynamic (PD) profiles of suvorexant (MK-4305); a dual orexin receptor antagonist, in healthy male subjects. / Clin Pharmacol Ther 2012,91(Suppl 1):S29.
41. Gilberto DB, Zeoli AH, Szczerba PJ, Gehret JR, Holahan MA, Sitko GR, Johnson CA, Cook JJ, Motzel SL: An alternative method of chronic cerebrospinal fluid collection via the cisterna magna in conscious rhesus monkeys. / Contemp Top Lab Anim Sci 2003, 42:53-9.
42. Renger JJ, Dunn SL, Motzel SL, Johnson C, Koblan KS: Sub-chronic administration of zolpidem affects modifications to rat sleep architecture. / Brain Res 2004, 1010:45-4. CrossRef
43. Malherbe P, Borroni E, Pinard E, Wettstein JG, Knoflach F: Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: comparison with selective OX1 and OX2 antagonists. / Mol Pharmacol 2009, 76:618-31. CrossRef
44. Dingemanse J, Dorffner G, Hajak G, Benes H, Danker-Hopfe H, Polo O, Saletu B, Barbanoj MJ, Pillar G, Penzel T, Chiossi E, Hoever P: Proof-of-concept study in primary insomnia patients with ACT-078573, a dual orexin receptor antagonist [abstract]. / Sleep Biol Rhythms [5th World Congr World Fed Sleep Res Sleep Med Soc] 2007., 5(Suppl): A194 - 作者单位：Anthony L Gotter (1)
Christopher J Winrow (1)
Joseph Brunner (1)
Susan L Garson (1)
Steven V Fox (2)
Jacquelyn Binns (2)
Charles M Harrell (1)
Donghui Cui (3)
Ka Lai Yee (3)
Mark Stiteler (2)
Joanne Stevens (2)
Alan Savitz (2)
Pamela L Tannenbaum (2)
Spencer J Tye (2)
Terrence McDonald (1)
Leon Yao (2)
Scott D Kuduk (4)
Jason Uslaner (2)
Paul J Coleman (4)
John J Renger (1)
1. Department of Neuroscience, Merck Research Laboratories, West Point, PA, USA
2. Department of In Vivo Pharmacology, Merck Research Laboratories, West Point, PA, USA
3. Department of Pharmacokinetics and Drug Metabolism, Merck Research Laboratories, West Point, PA, USA
4. Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA, USA
文摘
Background Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound’s mechanism of action. Results Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. Conclusion The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8?h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.