Kinetic properties of "dual" orexin receptor antagonists at OX1R and OX2R orexin receptors

Frontiers in Neuroscience

Volumn , Issue 7 DEC, 2013, Pages

  Callander, Gabrielle E ^a,b   Olorunda, Morenike ^c   Monna, Dominique ^c   Schuepbach, Edi ^c   Langenegger, Daniel ^c   Betschart, Claudia ^c   Hintermann, Samuel ^c   Behnke, Dirk ^c   Cotesta, Simona ^c   Fendt, Markus ^c,e   Laue, Grit ^c   Ofner, Silvio ^c   Briard, Emmanuelle ^c   Gee, Christine E ^c,d   Jacobson, Laura H ^b,c   Hoyer, Daniel ^a,b,c  

^a UNIVERSITY OF MELBOURNE   (Australia)

^b UNIVERSITY OF MELBOURNE   (Australia)

^c NOVARTIS PHARMA AG   (Switzerland)

^d Institute for Physiological Chemistry   (Germany)

^e OTTO VON GUERICKE UNIVERSITY   (Germany)

Author keywords

Dual orexin receptor antagonists; Kinetics; Orexin receptor antagonists; Radioligands

Indexed keywords

ALMOREXANT; CALCIUM; FILOREXANT; IMIDAZOLE DERIVATIVE; N [(1,1' BIPHENYL) 2 YL] 1 [2 [(1 METHYL 1H BENZO[D]IMIDAZOL 2 YL)THIO]ACETY]PYRROLIDINE 2 CARBOXAMIDE; OREXIN 1 RECEPTOR; OREXIN 2 RECEPTOR; OREXIN RECEPTOR ANTAGONIST; PYRIMIDINE DERIVATIVE; RADIOLIGAND; RECEPTOR BLOCKING AGENT; SB 649868; SUVOREXANT; UNCLASSIFIED DRUG; [2 [(1H INDOL 3 YL)METHYL] 9 (4 METHOXYPYRIMIDIN 2 YL) 2,9 DIAZASPIRO[5.5]UNDECAN 1 ONE;

ANIMAL CELL; ARTICLE; BINDING AFFINITY; BINDING COMPETITION; CONCENTRATION RESPONSE; DRUG COMPETITION; DRUG RECEPTOR BINDING; DRUG SELECTIVITY; FEMALE; HOMEOSTASIS; IC 50; IN VITRO STUDY; LIGAND BINDING; NONHUMAN; PHARMACOKINETICS; PROTEIN EXPRESSION; RECEPTOR OCCUPANCY; STEADY STATE;

EID: 84898044015     PISSN: 16624548     EISSN: 1662453X     Source Type: Journal    
DOI: 10.3389/fnins.2013.00230     Document Type: Article

References (63)

1. Besset, A., Tafti, M., Villemin, E., Borderies, P., and Billiard, M. (1995). Effects of zolpidem on the architecture and cyclical structure of sleep in poor sleepers. Drugs Exp. Clin. Res. 21, 161-169.
2. Betschart, C., Hintermann, S., Behnke, D., Cotesta, S., Fendt, M., Gee, C. E., et al. (2013). Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia. J. Med. Chem. 56, 7590-7607. doi: 10.1021/jm4007627
3. Bettica, P., Nucci, G., Pyke, C., Squassante, L., Zamuner, S., Ratti, E., et al. (2012a). Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist. J. Psychopharmacol. 26, 1058-1070. doi: 10.1177/0269881111408954
4. Bettica, P., Squassante, L., Groeger, J. A., Gennery, B., Winsky-Sommerer, R., and Dijk, D. J. (2012b). 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 37, 1224-1233. doi: 10.1038/npp.2011.310
5. Bettica, P., Squassante, L., Zamuner, S., Nucci, G., Danker-Hopfe, H., and Ratti, E. (2012c). The orexin antagonist SB-649868 promotes and maintains sleep in men with primary insomnia. Sleep 35, 1097-1104. doi: 10.5665/sleep.1996
6. Bettica, P. U., Lichtenfeld, U., Squassante, L., Shabbir, S., Zuechner, D., Dreykluft, P., et al. (2009a). The orexin antagonist SB-649868 promotes and maintains sleep in healthy volunteers and in patients with primary insomnia. Sleep 32, A252-A253.
7. Bettica, P. U., Squassante, L., Groeger, J. A., Gennery, B., and Dijk, D. (2009b). Hypnotic effects of SB-649868, an orexin antagonist, and zolpidem in a model of situational insomnia. Sleep 32, A40.
8. Beuckmann, C. T., Sinton, C. M., Williams, S. C., Richardson, J. A., Hammer, R. E., Sakurai, T., et al. (2004). Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J. Neurosci. 24, 4469-4477. doi: 10.1523/jneurosci.5560-03.2004
9. Beuckmann, C. T., Willie, J. T., Hara, J., Yamanaka, A., Sakurai, T., and Yanagisawa, M. (2002). Orexin neuron-ablated mice fail to increase vigilance and locomotor activity in response to fasting. Sleep 25, A353-A354.
10. Black, S. W., Morairty, S. R., Fisher, S. P., Chen, T. M., Warrier, D. R., and Kilduff, T. S. (2013). Almorexant promotes sleep and exacerbates cataplexy in a murine model of narcolepsy. Sleep 36, 325-336. doi: 10.5665/sleep.2442
11. Brisbare-Roch, C., Dingemanse, J., Koberstein, R., Hoever, P., Aissaoui, H., Flores, S., et al. (2007). Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat. Med. 13, 150-155. doi: 10.1038/nm1544
12. Buysse, D. J. (2013). Insomnia. J. Am. Med. Assoc. 309, 706-716. doi: 10.1001/jama.2013.193
13. Chemelli, R. M., Willie, J. T., Sinton, C. M., Elmquist, J. K., Scammell, T., Lee, C., et al. (1999). Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98, 437-451. doi: 10.1016/s0092-8674(00)81973-x
14. Cheng, Y., and Prusoff, W. H. (1973). Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem. Pharmacol. 22, 3099-3108.
15. Coleman, P. J., Schreier, J. D., Cox, C. D., Breslin, M. J., Whitman, D. B., Bogusky, M. J., et al. (2012). 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 7, 415-424. doi: 10.1002/cmdc.201200025
16. Connor, K., Budd, K., Snavely, D., Liu, K., Hutzel-Mann, J., Benca, R., et al. (2012). Efficacy and safety of suvorexant, an orexin receptor antagonist, in patients with primary insomnia: a 3-month phase 3 trial (trial #1). J. Sleep Res. 21, 97.
17. Cox, C. D., Breslin, M. J., Whitman, D. B., Schreier, J. D., McGaughey, G. B., Bogusky, M. J., et al. (2010). Discovery of the dual orexin receptor antagonist (7R)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl 5-met hyl-2-(2H-1,2,3-triazol-2-yl)phenyl methanone (MK-4305) for the treatment of Insomnia. J. Med. Chem. 53, 5320-5332. doi: 10.1021/jm100541c
18. de Lecea, L., Kilduff, T. S., Peyron, C., Gao, X. B., Foye, P. E., Danielson, P. E., et al. (1998). The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A. 95, 322-327. doi: 10.1073/pnas.95.1.322
19. Farkas, R. (2013). Suvorexant Safety and Efficacy [Online]. www.fda.gov: U.S. Food and Drug Administration. Available online at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM354215.pdf (Accessed on May 08,2013).
20. Fox, S. V., Gotter, A. L., Tye, S. J., Garson, S. L., Savitz, A. T., Uslaner, J. M., et al. (2013). Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats. Neuropsychopharmacology 38, 2401-2408. doi: 10.1038/npp.2013.139
21. Gotter, A. L., Roecker, A. J., Hargreaves, R., Coleman, P. J., Winrow, C. J., and Renger, J. J. (2012). "Orexin receptors as therapeutic drug targets," in Orexin/Hypocretin System, ed Shekhar, A. (Amsterdam: Elsevier Science Bv), 163-188.
22. Greenblatt, D. J., Harmatz, J. S., von Moltke, L. L., Ehrenberg, B. L., Harrel, L., Corbett, K., et al. (1998). Comparative kinetics and dynamics of zaleplon, zolpidem, and placebo. Clin. Pharmacol. Ther. 64, 553-561. doi: 10.1016/S0009-9236(98)90139-4
23. Hara, J., Beuckmann, C. T., Nambu, T., Willie, J. T., Chemelli, R. M., Sinton, C. M., et al. (2001a). Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345-354. doi: 10.1016/s0896-6273(01)00293-8
24. Hara, J., Nambu, T., Beuckmann, C. T., Goto, K., Yanagisawa, M., and Sakurai, T. (2001b). Genetic ablation of orexin neurons in mice: a mouse model of narcolepsy. Sleep 24, A156.
25. Herring, W. J., Snyder, E., Budd, K., Hutzelmann, J., Snavely, D., Liu, K., et al. (2012a). Orexin receptor antagonism for treatment of insomnia a randomized clinical trial of suvorexant. Neurology 79, 2265-2274. doi: 10.1212/WNL.0b013e31827688ee
26. Herring, W. J., Snyder, E., Paradis, E., Hutzelmann, J., Liu, M. C., Snavely, D., et al. (2012b). Suvorexant, an orexin receptor antagonist, in preventing symptom return in patients with insomnia after 1 year of treatment: a randomised, double-blind, placebo-controlled study. J. Sleep Res. 21, 351-351.
27. Hoever, P., de Haas, S., Dorffner, G., Chiossi, E., van Gerven, J., and Dingemanse, J. (2012). Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J. Psychopharmacol. 26, 1071-1080. doi: 10.1177/0269881112448946
28. Hoyer, D., Dürst, T., Fendt, M., Jacobson, L. H., Betschart, C., Hintermann, S., et al. (2013). Distinct effects of IPSU and suvorexant on mouse sleep architecture. Front. Neurosci. 7:235. doi: 10.3389/fnins.2013.00235
29. Ivgy-May, N., Leibensperger, H., Froman, S., Hutzelmann, J., Snavely, D., Snyder, E., et al. (2012). Efficacy and safety of suvorexant, an orexin receptor antagonist, in patients with primary insomnia: a 3-month phase 3 trial (trial #2). J. Sleep Res. 21, 351-352.
30. Kalogiannis, M., Hsu, E., Willie, J. T., Chemelli, R. M., Kisanuki, Y. Y., Yanagisawa, M., et al. (2011). Cholinergic modulation of narcoleptic attacks in double orexin receptor knockout mice. PLoS ONE 6:e18697. doi: 10.1371/journal.pone.0018697
31. Lin, L., Faraco, J., Li, R., Kadotani, H., Rogers, W., Lin, X. Y., et al. (1999). The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 98, 365-376. doi: 10.1016/s0092-8674(00)81965-0
32. Malherbe, P., Borroni, E., Pinard, E., Wettstein, J. G., and Knoflach, F. (2009). biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX(1))/orexin 2 receptor (OX(2)) antagonist: comparison with selective OX(1) and OX(2) antagonists. Mol. Pharmacol. 76, 618-631. doi: 10.1124/mol.109.055152
33. Malherbe, P., Roche, O., Marcuz, A., Kratzeisen, C., Wettstein, J. G., and Bissantz, C. (2010). Mapping the binding pocket of dual antagonist almorexant to human orexin 1 and orexin 2 receptors: comparison with the selective OX1 antagonist SB-674042 and the selective OX2 antagonist N-ethyl-2-(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino-N-pyridi n-3-ylmethyl-acetamide (EMPA). Mol. Pharmacol. 78, 81-93. doi: 10.1124/mol.110.064584
34. Mang, G. M., Durst, T., Burki, H., Imobersteg, S., Abramowski, D., Schuepbach, E., et al. (2012). The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 35, 1625-1635. doi: 10.5665/sleep.2232
35. Marcus, J. N., Aschkenasi, C. J., Lee, C. E., Chemelli, R. M., Saper, C. B., Yanagisawa, M., et al. (2001). Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol. 435, 6-25. doi: 10.1002/cne.1190.
36. Merck Sharp Dohme Corporation. (2013a). Suvorexant Advisory Committee Briefing Document. Available online at: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM352970.pdf
37. Merck Sharp Dohme Corporation. (2013b). Merck Receives Complete Response Letter for Suvorexant, Merck's Investigational Medicine for Insomnia. Available online at: http://www.mercknewsroom.com/press-release/research-and-development-news/merck-receives-complete-response-letter-suvorexant-merck.
38. Morairty, S. R., Revel, F. G., Malherbe, P., Moreau, J. L., Valladao, D., Wettstein, J. G., et al. (2012). Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PLoS ONE 7:e39131. doi: 10.1371/journal.pone.0039131
39. Nishino, S., Ripley, B., Overeem, S., Lammers, G. J., and Mignot, E. (2000). Hypocretin (orexin) deficiency in human narcolepsy. Lancet 355, 39-40. doi: 10.1016/s0140-6736(99)05582-8
40. Owen, R. T., Castaner, R., Bolos, J., and Estivill, C. (2009). Almorexant dual orexin OX1/OX2 antagonist treatment of sleep disorders. Drugs Future 34, 5-10. doi: 10.1358/dof.2009.034.01.1324392
41. Peyron, C., Tighe, D. K., van den Pol, A. N., de Lecea, L., Heller, H. C., Sutcliffe, J. G., et al. (1998). Neurons containing hypocretin (orexin) project to multiple neuronal systems. J. Neurosci. 18, 9996-10015.
42. Radl, S. (2013). SUVOREXANT dual orexin OX1/OX2 receptor antagonist treatment of sleep disorders. Drugs Future 38, 27-36. doi: 10.1358/dof.2013.38.1.1906425
43. Roecker, A. J., and Coleman, P. J. (2008). Orexin receptor antagonists: medicinal chemistry and therapeutic potential. Curr. Top. Med. Chem. 8, 977-987. doi: 10.2174/156802608784936746
44. Roth, T., Roehrs, T., and Vogel, G. (1995). Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. Sleep 18, 246-251.
45. Sakurai, T. (2007). The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat. Rev. Neurosci. 8, 171-181. doi: 10.1038/nrn2092
46. Sakurai, T., Amemiya, A., Ishii, M., Matsuzaki, I., Chemelli, R. M., Tanaka, H., et al. (1998). Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573-585. doi: 10.1016/s0092-8674(00)80949-6
47. Scammell, T. E., Estabrooke, I. V., McCarthy, M. T., Chemelli, R. M., Yanagisawa, M., Miller, M. S., et al. (2000). Hypothalamic arousal regions are activated during modafinil-induced wakefulness. J. Neurosci. 20, 8620-8628.
48. Scammell, T. E., and Winrow, C. J. (2011). Orexin receptors: pharmacology and therapeutic opportunities. Annu. Rev. Pharmacol. Toxicol. 51, 243-266. doi: 10.1146/annurev-pharmtox-010510-100528
49. Scatchard, G. (1949). The attractions of proteins for small molecules and ions. Ann. N.Y. Acad. Sci. 51, 660-672. doi: 10.1111/j.1749-6632.1949.tb27297.x
50. Sherin, J. E., Elmquist, J. K., Torrealba, F., and Saper, C. B. (1998). Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J. Neurosci. 18, 4705-4721.
51. Sun, H., Kennedy, W. P., Wilbraham, D., Lewis, N., Calder, N., Li, X. D., et al. (2013). Effects of suvorexant, an orexin receptor antagonist, on sleep parameters as measured by polysomnography in healthy men. Sleep 36, 259-267. doi: 10.5665/sleep.2386
52. Tafti, M. (2007). Reply to 'Promotion of sleep by targeting the orexin system in rats, dogs and humans'. Nat. Med. 13, 525-526. doi: 10.1038/nm0507-525
53. Tafti, M., Maret, S., and Dauvilliers, Y. (2005). Genes for normal sleep and sleep disorders. Ann. Med. 37, 580-589. doi: 10.1080/07853890500372047
54. Tang, J., Chen, J., Ramanjaneya, M., Punn, A., Conner, A. C., and Randeva, H. S. (2008). The signalling profile of recombinant human orexin-2 receptor. Cell. Signal. 20, 1651-1661. doi: 10.1016/j.cellsig.2008.05.010
55. Thannickal, T. C., Moore, R. Y., Nienhuis, R., Ramanathan, L., Gulyani, S., Aldrich, M., et al. (2000). Reduced number of hypocretin neurons in human narcolepsy. Neuron 27, 469-474. doi: 10.1016/s0896-6273(00)00058-1
56. Trivedi, P., Yu, H., MacNeil, D. J., Van der Ploeg, L. H. T., and Guan, X. M. (1998). Distribution of orexin receptor mRNA in the rat brain. FEBS Lett. 438, 71-75. doi: 10.1016/s0014-5793(98)01266-6
57. Uslaner, J. M., Tye, S. J., Eddins, D. M., Wang, X., Fox, S. V., Savitz, A. T., et al. (2013). Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition. Sci. Transl. Med. 5, 179ra144. doi: 10.1126/scitranslmed.3005213
58. Willie, J. T., Chemelli, R. M., Sinston, C. M., Tokita, H., Williams, S. C., Kisanuki, Y. Y., et al. (2003). Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron 38, 715-730. doi: 10.1016/s0896-6273(03)00330-1
59. Wilson, S. J., Nutt, D. J., Alford, C., Argyropoulos, S. V., Baldwin, D. S., Bateson, A. N., et al. (2010). British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J. Psychopharmacol. 24, 1577-1601. doi: 10.1177/0269881110379307
60. Winrow, C. J., Gotter, A. L., Cox, C. D., Doran, S. M., Tannenbaum, P. L., Breslin, M. J., et al. (2011). Promotion of sleep by suvorexant-a novel dual orexin receptor antagonist. J. Neurogenet. 25, 52-61. doi: 10.3109/01677063.2011.566953
61. Winrow, C. J., Gotter, A. L., Cox, C. D., Tannenbaum, P. L., Garson, S. L., Doran, S. M., et al. (2012). Pharmacological characterization of MK-6096-A dual orexin receptor antagonist for insomnia. Neuropharmacology 62, 978-987. doi: 10.1016/j.neuropharm.2011.10.003
62. Yamanaka, A., Beuckmann, C. T., Willie, J. T., Hara, J., Tsujino, N., Mieda, M., et al. (2003). Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38, 701-713. doi: 10.1016/s0896-6273(03)00331-3
63. Zhu, Y., Miwa, Y., Yamanaka, A., Yada, T., Shibahara, M., Abe, Y., et al. (2003). Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and-insensitive G-proteins. J. Pharmacol. Sci. 92, 259-266. doi: 10.1254/jphs.92.259