Translational evaluation of novel selective orexin-1 receptor antagonist JNJ-61393215 in an experimental model for panic in rodents and humans

Giacomo Salvadore, Pascal Bonaventure*, Anantha Shekhar, Philip L. Johnson, Brian Lord, Brock T. Shireman, Terry P. Lebold, Diane Nepomuceno, Christine Dugovic, Sander Brooks, Rob Zuiker, Cathy Bleys, Kanaka Tatikola, Bart Remmerie, Gabriel E. Jacobs, Koen Schruers, John Moyer, Abigail Nash, Luc G. M. Van Nueten, Wayne C. Drevets

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Web of Science)

Abstract

Orexin neurons originating in the perifornical and lateral hypothalamic area project to anxiety- and panic-associated neural circuitry, and are highly reactive to anxiogenic stimuli. Preclinical evidence suggests that the orexin system, and particularly the orexin-1 receptor (OX1R), may be involved in the pathophysiology of panic and anxiety. Selective OX1R antagonists thus may constitute a potential new treatment strategy for panic- and anxiety-related disorders. Here, we characterized a novel selective OX1R antagonist, JNJ-61393215, and determined its affinity and potency for human and rat OX1R in vitro. We also evaluated the safety, pharmacokinetic, and pharmacodynamic properties of JNJ-61393215 in first-in-human single- and multiple-ascending dose studies conducted. Finally, the potential anxiolytic effects of JNJ-61393215 were evaluated both in rats and in healthy men using 35% CO(2)inhalation challenge to induce panic symptoms. In the rat CO(2)model of panic anxiety, JNJ-61393215 demonstrated dose-dependent attenuation of CO2-induced panic-like behavior without altering baseline locomotor or autonomic activity, and had minimal effect on spontaneous sleep. In phase-1 human studies, JNJ-61393215 at 90 mg demonstrated significant reduction (P <0.02) in CO2-induced fear and anxiety symptoms that were comparable to those obtained using alprazolam. The most frequently reported adverse events were somnolence and headache, and all events were mild in severity. These results support the safety, tolerability, and anxiolytic effects of JNJ-61393215, and validate CO(2)exposure as a translational cross-species experimental model to evaluate the therapeutic potential of novel anxiolytic drugs.

Original languageEnglish
Article number308
Number of pages10
JournalTranslational Psychiatry
Volume10
Issue number1
DOIs
Publication statusPublished - 7 Sep 2020

Keywords

  • OREXIN/HYPOCRETIN SYSTEM
  • SLEEP
  • STRESS
  • RESPONSES
  • BLOCKADE
  • ANXIETY
  • PROMOTION
  • HEALTHY
  • NEURONS
  • RAT

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