A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects

Journal of Pharmacology and Experimental Therapeutics

Volumn 352, Issue 3, 2015, Pages 590-601

  Bonaventure, Pascal ^a   Yun, Sujin ^a   Johnson, Philip L ^b   Shekhar, Anantha ^b   Fitz, Stephanie D ^b   Shireman, Brock T ^a   Lebold, Terry P ^a   Nepomuceno, Diane ^a   Lord, Brian ^a   Wennerholm, Michelle ^a   Shelton, Jonathan ^a   Carruthers, Nicholas ^a   Lovenberg, Timothy ^a   Dugovic, Christine ^a  

^a JANSSEN RESEARCH AND DEVELOPMENT   (Belgium)

^b INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (2 METHYL 6 BENZOXAZOLYL) 3 (1,5 NAPHTHYRIDIN 4 YL)UREA; 1 (6,8 DIFLUORO 2 METHYLQUINOLIN 4 YL) 3 [4 (DIMETHYLAMINO)PHENYL]UREA; 5 BROMO N [[1 [(3 FLUORO 2 METHOXYPHENYL)CARBONYL] 5 METHYLPIPERIDIN 2 YLMETHYL]PYRIDIN 2 AMINE]; AGENTS INTERACTING WITH TRANSMITTER, HORMONE OR DRUG RECEPTORS; HORMONE RECEPTOR AFFECTING AGENT; HORMONE RECEPTOR BLOCKING AGENT; N [[3 [(3 ETHOXY 6 METHYLPYRIDIN 2 YL)CARBONYL] 3 AZABICYCLO[4.1.0]HEPT 4 YL]METHYL] 5 (TRIFLUOROMETHYL)PYRIMIDIN 2 AMINE; OREXIN 1 RECEPTOR; UNCLASSIFIED DRUG; 5-BROMO-N-(1-(3-FLUORO-2-METHOXYBENZOYL)-5-METHYLPIPERIDIN-2-YL)METHYLPYRIDIN-2-AMINE; AMINOPYRIDINE DERIVATIVE; HYPNOTIC SEDATIVE AGENT; OREXIN RECEPTOR; OREXIN RECEPTOR ANTAGONIST; PIPERIDINE DERIVATIVE; PROTEIN BINDING;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AROUSAL; ARTICLE; BINDING AFFINITY; BLOOD BRAIN BARRIER; CARDIOVASCULAR RESPONSE; CONTROLLED STUDY; DRUG MECHANISM; DRUG PENETRATION; DRUG RECEPTOR BINDING; DRUG STRUCTURE; EMBRYO; EX VIVO STUDY; HUMAN; HUMAN CELL; IN VIVO STUDY; MALE; MENTAL STRESS; MOUSE; NONHUMAN; PANIC; RAT; RECEPTOR OCCUPANCY; REM SLEEP; SLEEP TIME; ANIMAL; C57BL MOUSE; CHO CELL LINE; CRICETULUS; DRUG EFFECTS; HAMSTER; HEK293 CELL LINE; KNOCKOUT MOUSE; METABOLISM; PHYSIOLOGY; PREVENTION AND CONTROL; SPRAGUE DAWLEY RAT;

AMINOPYRIDINES; ANIMALS; AROUSAL; CHO CELLS; CRICETINAE; CRICETULUS; HEK293 CELLS; HUMANS; HYPNOTICS AND SEDATIVES; MALE; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; OREXIN RECEPTOR ANTAGONISTS; OREXIN RECEPTORS; PIPERIDINES; PROTEIN BINDING; RATS; RATS, SPRAGUE-DAWLEY; STRESS, PSYCHOLOGICAL;

EID: 84922365638     PISSN: 00223565     EISSN: 15210103     Source Type: Journal    
DOI: 10.1124/jpet.114.220392     Document Type: Article

References (44)

1. Abshire VM, Hankins KD, Roehr K.E., and DiMicco JA (1988) Injection of L-allylglycine into the posterior hypothalamus in rats causes decreases in local GABA which correlate with increases in heart rate. Neuropharmacology 27:1171-1177.
2. Alvaro G, Amantini D, Castiglioni E., Di Fabio R and Pavone F (2010) inventors, Glaxo Group Limited UK, assignee. N-{[(1S,4S,6S)-3-(2-Pyridinylcarbonyl)-3-azabicyclo [4.1.0]hept-4-yl]methyl}-2-heteroarylamine derivatives as orexin receptor antagonists and their preparation and use for the treatment of diseases. WO2010063662A1
3. Berridge CW, España RA, and Vittoz NM (2010) Hypocretin/orexin in arousal and stress. Brain Res 1314:91-102.
4. Cano G, Mochizuki T, and Saper CB (2008) Neural circuitry of stress-induced insomnia in rats. J Neurosci 28:10167-10184.
5. Chang H, Saito T, Ohiwa N., Tateoka M, Deocaris CC, Fujikawa T, and Soya H (2007) Inhibitory effects of an orexin-2 receptor antagonist on orexin A- and stress-induced ACTH responses in conscious rats. Neurosci Res 57:462-466.
6. Cheng Y and Prusoff WH (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.
7. de Lecea L, Kilduff TS, Peyron C, Gao X., Foye PE, Danielson PE, Fukuhara C, Battenberg E.L., Gautvik VT, Bartlett FS, 2nd, et al. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322-327.
8. Dugovic C, Shelton JE, Aluisio L.E., Fraser IC, Jiang X, Sutton SW, Bonaventure P, Yun S., Li X, Lord B, et al. (2009) Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther 330:142-151.
9. Dugovic C, Shelton JE, Yun S, Bonaventure P., Shireman BT, and Lovenberg TW (2014) Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism. Front Neurosci 8:28.
10. Furlong TM, Vianna DM, Liu L, and Carrive P (2009) Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal. Eur J Neurosci 30: 1603-1614.
11. Gozzi A, Turrini G, Piccoli L., Massagrande M, Amantini D, Antolini M., Martinelli P, Cesari N, Montanari D., Tessari M, et al. (2011) Functional magnetic resonance imaging reveals different neural substrates for the effects of orexin-1 and orexin-2 receptor antagonists. PLoS ONE 6:e16406.
12. Hoyer D and Jacobson LH (2013) Orexin in sleep, addiction and more: is the perfect insomnia drug at hand? Neuropeptides 47:477-488.
13. Johnson PL, Samuels BC, Fitz S.D., Federici LM, Hammes N, Early MC, Truitt W, Lowry C.A., and Shekhar A (2012) Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav 107:733-742.
14. Johnson PL and Shekhar A (2012) An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus. Physiol Behav 107:686-698.
15. Johnson PL, Truitt WA, Fitz S.D., Lowry CA, and Shekhar A (2008) Neural pathways underlying lactate-induced panic. Neuropsychopharmacology 33:2093-2107.
16. Johnson PL, Truitt W, Fitz S.D., Minick PE, Dietrich A, Sanghani S, Träskman-Bendz L, Goddard AW, Brundin L, and Shekhar A (2010) A key role for orexin in panic anxiety. Nat Med 16:111-115.
17. Langmead CJ, Jerman JC, Brough S.J., Scott C., Porter RA, and Herdon HJ (2004) Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol 141:340-346.
18. Lee DL, Webb RC, and Brands MW (2004) Sympathetic and angiotensin-dependent hypertension during cage-switch stress in mice. Am J Physiol Regul Integr Comp Physiol 287:R1394-R1398.
19. Li J, Hu Z, and de Lecea L (2014) The hypocretins/orexins: integrators of multiple physiological functions. Br J Pharmacol 171:332-350.
20. Malherbe P, Borroni E, Gobbi L., Knust H, Nettekoven M, Pinard E., Roche O, Rogers-Evans M, Wettstein JG, and Moreau JL (2009) Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol 156:1326-1341.
21. Mang GM, Dürst T, Bürki H, Imobersteg S., Abramowski D, Schuepbach E, Hoyer D., Fendt M, and Gee CE (2012) The dual orexin receptor antagonist almorexant induces sleep and decreases orexin-induced locomotion by blocking orexin 2 receptors. Sleep 35:1625-1635.
22. Marcus JN, Aschkenasi CJ, Lee C.E., Chemelli RM, Saper CB, Yanagisawa M, and Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6-25.
23. Maton W, Stazi F, Manzo A., Pachera R, Ribecai A, Stabile P., Perboni A, Giubellina N, Bravo F., Castoldi D, et al. (2010) An efficient scalable route for the synthesis of enantiomerically pure tert-Butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0] heptane-3-carboxylate. Org Process Res Dev 14:1239-1247.
24. McElhinny CJ, Jr, Lewin AH, Mascarella SW, Runyon S, Brieaddy L, and Carroll FI (2012) Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies. Bioorg Med Chem Lett 22:6661-6664.
25. Oka T, Oka K, Kobayashi T., Sugimoto Y, Ichikawa A, Ushikubi F., Narumiya S, and Saper CB (2003) Characteristics of thermoregulatory and febrile responses in mice deficient in prostaglandin EP1 and EP3 receptors. J Physiol 551:945-954.
26. Paxinos G and Watson C (2005) The Rat Brain in Stereotaxic Coordinates, Elsevier Academic Press, San Diego, CA.
27. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, and Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996-10015.
28. Sakurai T, Amemiya A, Ishii M., Matsuzaki I, Chemelli RM, Tanaka H, Williams S.C., Richarson JA, Kozlowski GP, Wilson S, 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.
29. Samuels BC, Zaretsky DV, and DiMicco JA (2004) Dorsomedial hypothalamic sites where disinhibition evokes tachycardia correlate with location of raphe-projecting neurons. Am J Physiol Regul Integr Comp Physiol 287:R472-R478.
30. Sanders SK and Shekhar A (1995) Regulation of anxiety by GABAA receptors in the rat amygdala. Pharmacol Biochem Behav 52:701-706.
31. Sharf R, Sarhan M, and Dileone RJ (2010) Role of orexin/hypocretin in dependence and addiction. Brain Res 1314:130-138.
32. Shekhar A and DiMicco JA (1987) Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats. Neuropharmacology 26:407-417.
33. Shekhar A, Johnson PL, Sajdyk T.J., Fitz SD, Keim SR, Kelley PE, Gehlert D.R., and DiMicco JA (2006) Angiotensin-II is a putative neurotransmitter in lactate-induced panic-like responses in rats with disruption of GABAergic inhibition in the dorsomedial hypothalamus. J Neurosci 26:9205-9215.
34. Shekhar A and Katner JS (1995) Dorsomedial hypothalamic GABA regulates anxiety in the social interaction test. Pharmacol Biochem Behav 50:253-258.
35. Shekhar A and Keim SR (1997) The circumventricular organs form a potential neural pathway for lactate sensitivity: implications for panic disorder. J Neurosci 17:9726-9735.
36. Shekhar A, Keim SR, Simon J.R., and McBride WJ (1996) Dorsomedial hypothalamic GABA dysfunction produces physiological arousal following sodium lactate infusions. Pharmacol Biochem Behav 55:249-256.
37. Smart D, Sabido-David C, Brough S.J., Jewitt F., Johns A, Porter RA, and Jerman JC (2001) SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 132:1179-1182.
38. Smith MI, Piper DC, Duxon M.S., and Upton N (2003) Evidence implicating a role for orexin-1 receptor modulation of paradoxical sleep in the rat. Neurosci Lett 341:256-258.
39. Steiner MA, Gatfield J, Brisbare-Roch C, Dietrich H., Treiber A, Jenck F, and Boss C (2013a) Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist. ChemMedChem 8:898-903.
40. Steiner MA, Lecourt H, and Jenck F (2012) The brain orexin system and almorexant in fear-conditioned startle reactions in the rat. Psychopharmacology (Berl) 223:465-475.
41. Steiner MA, Sciarretta C, Brisbare-Roch C, Strasser D.S., Studer R., and Jenck F (2013b) Examining the role of endogenous orexins in hypothalamus-pituitary-adrenal axis endocrine function using transient dual orexin receptor antagonism in the rat. Psychoneuroendocrinology 38:560-571.
42. Trivedi P, Yu H, MacNeil D.J., Van der Ploeg LHT, and Guan X-M (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438:71-75.
43. Verdelet T, Mercey G, Correa N., Jean L, and Renard P-Y (2011) Straightforward and efficient synthesis of 3-benzyloxy-4-bromopicolinate ester and 3-benzyloxy-5-bromopicolinate ester, common building blocks for pharmaceuticals and agro-chemicals. Tetrahedron 67:8757-8762.
44. Yeoh JW, Campbell EJ, James M.H., Graham BA, and Dayas CV (2014) Orexin antagonists for neuropsychiatric disease: progress and potential pitfalls. Front Neurosci 8:36.