Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

doi:10.1016/j.biopsych.2016.10.012

Biological Psychiatry

Volume 82, Issue 9, 1 November 2017, Pages 623-633

https://doi.org/10.1016/j.biopsych.2016.10.012 Get rights and content

Abstract

Background

Narcolepsy, a disorder of rapid eye movement (REM) sleep, is characterized by excessive daytime sleepiness and cataplexy, a loss of muscle tone triggered by emotional stimulation. Current narcolepsy pharmacotherapeutics include controlled substances with abuse potential or drugs with undesirable side effects. As partial agonists at trace amine-associated receptor 1 (TAAR1) promote wakefulness in mice and rats, we evaluated whether TAAR1 agonism had beneficial effects in two mouse models of narcolepsy.

Methods

In the first experiment, male homozygous B6-Taar1^{tm1(NLSLacZ)Blt} (Taar1 knockout) and wild-type mice were surgically implanted to record electroencephalogram, electromyogram, locomotor activity, and body temperature, and the efficacy of the TAAR1 agonist, RO5256390, on sleep/wake and physiological parameters was determined. In the second experiment, the effects of the TAAR1 full agonist RO5256390 and partial agonist RO5263397 on sleep/wake, locomotor activity, body temperature, and cataplexy were assessed in two mouse narcolepsy models.

Results

RO5256390 profoundly reduced rapid eye movement sleep in wild-type mice; these effects were eliminated in Taar1 knockout mice. The TAAR1 partial agonist RO5263397 also promoted wakefulness and suppressed nonrapid eye movement sleep. Both compounds reduced body temperature in the two narcolepsy models at the highest doses tested. Both TAAR1 compounds also mitigated cataplexy, the pathognomonic symptom of this disorder, in the narcolepsy models. The therapeutic benefit was mediated through a reduction in number of cataplexy episodes and time spent in cataplexy.

Conclusions

These results suggest TAAR1 agonism as a new therapeutic pathway for treatment of this orphan disease. The common underlying mechanism may be the suppression of rapid eye movement sleep.

Section snippets

Methods and Materials

All experimental procedures were approved by the Institutional Animal Care and Use Committee at SRI International and were conducted in accordance with the principles set forth in the Guide for Care and Use of Laboratory Animals. Detailed methods are described in Supplemental Methods.

Protocol 1: Efficacy of Full and Partial TAAR1 Agonists in Taar1 KO and WT Mice

We previously showed that the TAAR1 partial agonist RO5263397 promoted wakefulness and inhibited REM sleep in mice and that these effects were TAAR1 dependent (38). To determine the generality of this response, we evaluated the efficacy of another TAAR1 agonist, RO5256390, on sleep/wake when administered to WT and Taar1 KO mice in the mid-light phase when mice normally spend most time asleep. Although we have previously characterized RO5256390 as a full agonist in rats and monkeys, its

Discussion

Narcolepsy is a disorder of REM sleep, and cataplexy is its pathognomonic symptom. In the present study, two TAAR1 agonists showed a therapeutic benefit in reduction of cataplexy in two different mouse models of narcolepsy. The TAAR1 partial agonist RO5263397 reduced cataplexy in both mouse narcolepsy models (Figure 5B, D, F) and suppressed REM sleep in the Atax narcolepsy model (Figure 3I, L) as well as in WT mice (Figure 1I). By contrast, RO5256390 had a therapeutic benefit on cataplexy (

Acknowledgments and Disclosures

This work was supported by the National Institutes of Health Grant Nos. R01 NS082876, R21 NS083639 and R21 NS085757 (to TSK).

We thank Professor Akihiro Yamanaka of Nagoya University for the C57BL/6-Tg(orexin/tTA; TetO diphtheria toxin A fragment)/Yamanaka mice. We also thank Drs. A. Harmeier, J.-L. Moreau, and J. Wettstein for valuable scientific input and Jeremiah Palmerston and Kelsie Bogyo for technical assistance.

MCH is an employee of F. Hoffmann-La Roche Ltd. Over the past 2 years, TSK has

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Trace amines, a group of amines expressed at the nanomolar level in the mammalian brain, can modulate monoamine transmission. The discovery of and the functional research on the trace amine-associated receptors (TAARs), especially the most well-characterized TAAR1, have largely facilitated our understanding of the function of the trace amine system in the brain. TAAR1 is expressed in the mammalian brain at a low level and widely distributed in the monoaminergic system, including the ventral tegmental area and substantial nigra, where the dopamine neurons reside in the mammalian brain. Growing in vitro and in vivo evidence has demonstrated that TAAR1 could negatively modulate monoamine transmission and play a crucial role in many psychiatric disorders, including schizophrenia, substance use disorders, sleep disorders, depression, and anxiety. Notably, in the last two decades, many studies have repeatedly confirmed the pharmacological effects of the selective TAAR1 ligands in various preclinical models of psychiatric disorders. Recent clinical trials of the dual TAAR1 and serotonin receptor agonist ulotaront also revealed a potential efficacy for treating schizophrenia. Here, we review the current understanding of the TAAR1 system and the recent advances in the elucidation of behavioral and physiological properties of TAAR1 agonists evaluated both in preclinical animal models and clinical trials. We also discuss the potential TAAR1-dependent signaling pathways and the cellular mechanisms underlying the inhibitory effects of TAAR1 activation on drug addiction. We conclude that TAAR1 is an emerging target for the treatment of psychiatric disorders.
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Ulotaront (SEP-363856) is a novel agonist at trace amine-associated receptor 1 and serotonin 5-HT_1A receptors in clinical development for the treatment of schizophrenia. Previous studies demonstrated ulotaront suppresses rapid eye movement (REM) sleep in both rodents and healthy volunteers. We assessed acute and sustained treatments of ulotaront on REM sleep and symptoms of cataplexy and alertness in subjects with narcolepsy-cataplexy.
In a multicenter, double-blind, placebo-controlled, randomized, 3-way crossover study, ulotaront was evaluated in 16 adults with narcolepsy-cataplexy. Two oral doses of ulotaront (25 mg and 50 mg) were administered daily for 2 weeks and compared with matching placebo (6-treatment sequence, 3-period, 3-treatment).
Acute treatment with both 25 mg and 50 mg of ulotaront reduced minutes spent in nighttime REM compared to placebo. A sustained 2-week administration of both doses of ulotaront reduced the mean number of short-onset REM periods (SOREMPs) during daytime multiple sleep latency test (MSLT) compared to placebo. Although cataplexy events decreased from the overall mean baseline during the 2-week treatment period, neither dose of ulotaront statistically separated from placebo (p = 0.76, 25 mg; p = 0.82, 50 mg), and no significant improvement in patient and clinician measures of sleepiness from baseline to end of the 2-week treatment period occurred in any treatment group.
Acute and sustained treatment with ulotaront reduced nighttime REM duration and daytime SOREMPs, respectively. The effect of ulotaront on suppression of REM did not demonstrate a statistical or clinically meaningful effect in narcolepsy-cataplexy.
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Trace amines (TAs) are metabolically related to catecholamine and associated with cancer and neurological disorders. Comprehensive measurement of TAs is essential for understanding pathological processes and providing proper drug intervention. However, the trace amounts and chemical instability of TAs challenge quantification. Here, diisopropyl phosphite coupled with chip two-dimensional (2D) liquid chromatography tandem triple-quadrupole mass spectrometry (LC-QQQ/MS) was developed to simultaneously determine TAs and associated metabolites. The results showed that the sensitivities of TAs increased up to 5520 times compared with those using nonderivatized LC-QQQ/MS. This sensitive method was utilized to investigate their alterations in hepatoma cells after treatment with sorafenib. The significantly altered TAs and associated metabolites suggested that phenylalanine and tyrosine metabolic pathways were related to sorafenib treatment in Hep3B cells. This sensitive method has great potential to elucidate the mechanism and diagnose diseases considering that an increasing number of physiological functions of TAs have been discovered in recent decades.
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Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor (GPCR) activated by trace amines (β-phenylethylamine, p-tyramine, tryptamine, and p-octopamine), 5-hydroxytryptamine (5-HT) and DA (partial agonists), and by a wide spectrum of psychoactive drugs, including amphetamine and its numerous analogs (Borowsky et al., 2001; Bunzow et al., 2001; Xie et al., 2007). TAAR1 has been shown to play a role in animal models of several neuropsychiatric conditions related to aberrant regulation of brain monoamines, such as substance use disorders (Liu and Li, 2018; Revel et al., 2012b), eating disorders (Ferragud et al., 2017; Moore et al., 2018), narcolepsy (Black et al., 2017), mood disorders (Mantas et al., 2021; Revel et al., 2012b, 2013; Zhang et al., 2021), Parkinson's disease (Alvarsson et al., 2015; Gemechu et al., 2018; Sotnikova et al., 2008), and schizophrenia (Kokkinou et al., 2020; Revel et al., 2012b, 2013). Ulotaront (SEP-363856), an agonist of TAAR1 and 5-HT type 1A receptor, is under clinical evaluation as a novel therapeutic agent for schizophrenia (Dodd et al., 2020).
Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has recently been implicated in several psychiatric conditions related to monoaminergic dysfunction, such as schizophrenia, substance use disorders, and mood disorders. Although attention-deficit/hyperactivity disorder (ADHD) is also related to changes in monoaminergic neurotransmission, studies that assess whether TAAR1 participates in the neurobiology of ADHD are lacking. We hypothesized that TAAR1 plays an important role in ADHD and might represent a potential therapeutic target. Here, we investigate if TAAR1 modulates behavioral phenotypes in Spontaneously Hypertensive Rats (SHR), the most validated animal model of ADHD, and Wistar Kyoto rats (WKY, used as a control strain). Our results showed that TAAR1 is downregulated in ADHD-related brain regions in SHR compared with WKY. While intracerebroventricular (i.c.v.) administration of the selective TAAR1 antagonist EPPTB impaired cognitive performance in SHR, i.c.v. administration of highly selective TAAR1 full agonist RO5256390 decreased motor hyperactivity, novelty-induced locomotion, and induced an anxiolytic-like behavior. Overall, our findings show that changes in TAAR1 levels/activity underlie behavior in SHR, suggesting that TAAR1 plays a role in the neurobiology of ADHD. Although additional confirmatory studies are required, TAAR1 might be a potential pharmacological target for individuals with this disorder.
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¹: SWB and MDS contributed equally to this work.

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Priority CommunicationTrace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics

Abstract

Background

Methods

Results

Conclusions

Section snippets

Methods and Materials

Protocol 1: Efficacy of Full and Partial TAAR1 Agonists in Taar1 KO and WT Mice

Discussion

Acknowledgments and Disclosures

Narcolepsy: Neural mechanisms of sleepiness and cataplexy

J Neurosci

A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains

Nat Med

Reduced number of hypocretin neurons in human narcolepsy

Neuron

Hypocretin (orexin) deficiency in human narcolepsy

Lancet

Relationship between CSF hypocretin levels and hypocretin neuronal loss

Exp Neurol

The development of hypocretin (orexin) deficiency in hypocretin/ataxin-3 transgenic rats

Neuroscience

Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation

Cell

The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene

Cell

Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: Molecular genetic dissection of Non-REM and REM sleep regulatory processes

Neuron

Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat

J Neurosci

Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity

Neuron

Conditional ablation of orexin/hypocretin neurons: A new mouse model for the study of narcolepsy and orexin system function

J Neurosci

Dopaminergic regulation of sleep and cataplexy in a murine model of narcolepsy

Sleep

Narcolepsy: Diagnosis and management

Dopaminergic role in stimulant-induced wakefulness

J Neurosci

Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro

J Pharmacol Exp Ther

Pharmacological aspects of human and canine narcolepsy

Prog Neurobiol

Narcolepsy: Pathophysiology and genetic predisposition

Reconsidering GHB: orphan drug or new model antidepressant?

J Psychopharmacol

Narcolepsy and effectiveness of gamma-hydroxybutyrate (GHB): A systematic review and meta-analysis of randomized controlled trials

Sleep Med Rev

Trace amines: Identification of a family of mammalian G protein-coupled receptors

Proc Natl Acad Sci U S A

Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor

Mol Pharmacol

Trace amine-associated receptor 1 modulates dopaminergic activity

J Pharmacol Exp Ther

The trace amine 1 receptor knockout mouse: An animal model with relevance to schizophrenia

Genes Brain Behav

Priority Communication
Trace Amine-Associated Receptor 1 Agonists as Narcolepsy Therapeutics