A Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal without Hypnotic Effects

Abstract

Orexins (OXs) are peptides produced by perifornical (PeF) and lateral hypothalamic neurons that exert a prominent role in arousal-related processes, including stress. A critical role for the orexin-1 receptor (OX1R) in complex emotional behavior is emerging, such as overactivation of the OX1R pathway being associated with panic or anxiety states. Here we characterize a brain-penetrant, selective, and high-affinity OX1R antagonist, Although compound 56 did not alter spontaneous sleep in rats and in wildtype mice, its administration in orexin-2 receptor knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. In a rat model of psychological stress induced by cage exchange, the OX1R antagonist prevented the prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the PeF OX region) to threatening internal state changes (i.e., intravenous sodium lactate infusion), compound 56 attenuated sodium lactate-induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress or hyperarousal states.

Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist

“…Our results strongly indicate that REM sleep increase is caused via OX 1 R antagonism. This result is in alignment with orexin receptor KO mouse studies, 40,41 which demonstrate that both receptors are involved in sleep/ wake regulation, with OX 2 R more regulating non-REM sleep and OX 1 R more regulating REM sleep. In addition, another sleep study, where orexin receptors were functionally inabled by pharmacological intervention by applying OX 2 R selective or dual orexin receptor antagonists, has indicated similar results regarding the roles of OX 1 R and OX 2 R for sleep architecture.…”

Recent trends in orexin research—2010 to 2015

“…Further investigations with compound 5 by the same group of authors led to the conclusion that selective Ox1 receptor blockade attenuates effectively stress and panic/anxiety related readouts and could be an option for the treatment of various psychiatric disorders associated with stress. The results reported for 5 are similar to earlier results reported with 1-SORAs 6 or 8 and 9 [34]. Heptares recently disclosed the structure of one of their lead orexin receptor antagonist compounds HTL6641 (10) [20] [35], a dual antagonist with a predicted human half-life of 7 h, which would be significantly shorter than the experimental half-live of suvorexant (1) of 12 h. For night treatment (e.g.…”

Orexins and fear: implications for the treatment of anxiety disorders

“…Indeed, the blockade of OX2R seems to be sufficient to induce sleep, whereas OX1R antagonists are largely devoid of this adverse effect (Box 1) [76]. In agreement, new selective OX1R antagonists recently characterized, such as [N-({3-[(3-ethoxy-6-methylpyridin-2-yl)carbonyl]-3-azabicyclo[4.1.0]-hept-4-yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine] (compound 56) reduces anxiety-associated behavioral and physiological responses without hypnotic effects [77]. Therefore, the use of OX1R antagonists in clinical trials for anxiety disorders could minimize the incidence of somnolence and impairment to drive or operate heavy machinery that constitute the most common adverse effects with previous dual orexin antagonists (http:// www.fda.gov/downloads/.../UCM354215.pdf).…”