Abstract
Orexin neurons originating in the perifornical and lateral hypothalamic area are highly reactive to anxiogenic stimuli and have strong projections to anxiety and panic-associated circuitry. Recent studies support a role for the orexin system and in particular the orexin 1 receptor (OX1R) in coordinating an integrative stress response. However, no selective OX1R antagonist has been systematically tested in two preclinical models of using panicogenic stimuli that induce panic attack in the majority of people with panic disorder, namely an acute hypercapnia-panic provocation model and a model involving chronic inhibition of GABA synthesis in the perifornical hypothalamic area followed by intravenous sodium lactate infusion. Here we report on a novel brain penetrant, selective and high affinity OX1R antagonist JNJ-54717793 (1S,2R,4R)-7-([(3-fluoro-2-pyrimidin-2-ylphenyl)carbonyl]-N-[5-(trifluoromethyl)pyrazin-2-yl]-7-azabicyclo[2.2.1]heptan-2-amine). JNJ-54717793 is a high affinity/potent OX1R antagonist and has an excellent selectivity profile including 50 fold versus the OX2R. Ex vivo receptor binding studies demonstrated that after oral administration JNJ-54717793 crossed the blood brain barrier and occupied OX1Rs in the rat brain. While JNJ-54717793 had minimal effect on spontaneous sleep in rats and in wild-type mice, its administration in OX2R knockout mice, selectively promoted rapid eye movement sleep, demonstrating target engagement and specific OX1R blockade. JNJ-54717793 attenuated CO2 and sodium lactate induced panic-like behaviors and cardiovascular responses without altering baseline locomotor or autonomic activity. These data confirm that selective OX1R antagonism may represent a novel approach of treating anxiety disorders, with no apparent sedative effects.
Highlights
Orexin neurons are located in the perifornical and lateral hypothalamus of rodents (Peyron et al, 1998), and humans (Thannickal et al, 2007)
Panic disorder is characterized by recurrent spontaneous panic attacks, which can be reliably induced with interoceptive stimuli such as intravenous 0.5 M sodium lactate and 5 min of 5–7% hypercapnic gas exposure, which do not induce panic attacks in healthy controls (Pitts and McClure, 1967; Woods et al, 1988; Gorman et al, 1994)
Exposing healthy humans to higher concentrations of hypercapnic gas (i.e., 20% CO2 inhalation) will induce core features of panic attacks (Forsyth et al, 2000). These two panic paradigms can be modeled in rats: (1) chronic disinhibition of the perifornical hypothalamic area orexin region produces rats that are vulnerable to displaying panic-like responses to interoceptive stimuli, such as sodium lactate; and (2) exposing naïve rats to 20% hypercapnic gas exposure induces panic-associated responses
Summary
Orexin neurons are located in the perifornical and lateral hypothalamus of rodents (Peyron et al, 1998), and humans (Thannickal et al, 2007). These two panic paradigms can be modeled in rats: (1) chronic disinhibition of the perifornical hypothalamic area orexin region produces rats that are vulnerable to displaying panic-like responses to interoceptive stimuli, such as sodium lactate (see review, Johnson and Shekhar, 2012); and (2) exposing naïve rats to 20% hypercapnic gas exposure induces panic-associated responses Both panic models, using stimuli that signal a threatening internal body state change, activate OX neurons in the perifornical hypothalamic area (Williams et al, 2007; Johnson et al, 2010, 2012c,d) and increase panic associated behaviors (e.g., flight like locomotion and anxiety in a social interaction (SI) test and defensive burying test) and panic associated dyspnea (Hickman et al, 2016) and cardioexcitation (Johnson et al, 2010, 2012c,d, 2015). A separate paper describes the new OX1R antagonist JNJ-54717793 (Figure 1) synthesis, structure activity relationship, pharmacokinetics in preclinical species (Shireman et al, submitted)
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