Evaluation of JNJ-54717793 a Novel Brain Penetrant Selective Orexin 1 Receptor Antagonist in Two Rat Models of Panic Attack Provocation

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.

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

“…The efficacy observed in the rat CO 2 challenge is unlikely to be driven by nonspecific effects, as demonstrated by the lack of effect on baseline locomotor or autonomic activity, and by the lack of effect of the less active enantiomer JNJ-63821238. A high level of target engagement (>90%) was required to demonstrate efficacy in the CO 2 challenge, as previously observed with other OX1R antagonists (SB-334867, Compound 56 and JNJ-54717793) 11,12,28 . These findings are consistent with the hypothesized role of OX1R signaling in the mechanism underlying CO 2 challenge-induced fear, as exposing rats to higher concentration of CO 2 depolarizes orexin neurons by interacting with pH/CO 2 -chemosensitive K + channels 29 .…”

“…In contrast, OX1Rs are more selectively expressed in bed nucleus of the stria terminalis, amygdala, cingulate cortex, and the noradrenergic neurons of the locus coeruleus 8 . Consistent with the anatomical distribution of OX1R, a critical role for this receptor is emerging in complex emotional behavior, such as association of OX1R pathway overactivation with panic or anxiety states [9][10][11][12][13] .…”

“…The OX1R inhibition in amygdala is consistent with preclinical studies demonstrating that the orexin system is implicated in amygdala regulation of fear-associated learning 8 – 10 . In contrast, OX1R antagonists have minimal effect on sleep stages in rodents 11 , 12 . Overall, there is compelling evidence that overactivation of the OX1R pathway is associated with hyperexcited or hyperactive states; thus, conceptually, a selective OX1R antagonist might normalize overexcited networks without inducing sedation 12 .…”

“…In rats, we measured in vivo target engagement of JNJ-61393215 in the brain and its pharmacodynamic effects on sleep/wake cycles. In our previous studies, we have shown that while selective OX1R antagonism did not affect sleep-wake states, blockade of both OX1R and OX2R elicited a disinhibition of rapid eye movement (REM) sleep at the expense of non-REM (NREM) sleep in rodents 11,12,18 . Therefore, the effect of JNJ-61393215 on sleep was tested in OX2R-knockout (KO) mice to demonstrate in vivo functional target engagement.…”

Recent advances in understanding the roles of hypocretin/orexin in arousal, affect, and motivation

“…For example, in rodent models of panic, an extreme form of anxiety, animals with panic vulnerability treated with the OX 1 R antagonist compound 56 reduced panic-like behaviors in a sodium lactate model of panic induction 88 . Similarly, treatment with the OX 1 R antagonist JNJ-54717793 attenuates panic-like behavior and cardiovascular responses in both the sodium lactate model of panic and a carbon dioxide (CO 2 ) model of panic provocation 89 . Additional studies within the CO 2 model that screened selective Hcrt receptor antagonists (SORAs) and dual Hcrt receptor antagonists (DORAs) found that both a SORA1 (compound 56) and a DORA-12 attenuate anxiety-like behaviors but that a SORA2 did not 90 .…”