Trace amine-associated receptor 1 agonism promotes wakefulness without impairment of cognition in Cynomolgus macaques

Goonawardena, Anushka V.; Morairty, Stephen R.; Dell, Ryan; Orellana, Gabriel A.; Hoener, Marius C.; Wallace, Tanya L.; Kilduff, Thomas S.

doi:10.1038/s41386-019-0386-8

Cited by 17 publications

(8 citation statements)

References 43 publications

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“…Earlier work has shown that agonism at TAAR1 and 5-HT 1A receptors contributes to the mechanism of action of SEP-363856 2 . Consequently, the effects of SEP-363856 on REM sleep are in line with prior reports of REM suppression following treatment with selective TAAR1 agonists in mice, rats 8 , 13 , 14 , 16 and nonhuman primates 15 . Although more robust effects on REM suppression were reported with partial (versus a full) TAAR1 agonist in rodents 13 , 16 , additional studies with full agonists are needed to better understand these discrepancies.…”

Section: Discussionsupporting

confidence: 87%

“…This includes most antidepressants (selective serotonin reupdate inhibitors (SSRIs), selective norepinephrine reupdate inhibitors (SNRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants and monoamine oxidase inhibitors), muscarinic antagonists, selective 5-HT 1A agonists, antihistaminic agents (e.g. promethazine) and TAAR1 agonists 8 , 15 , 22 , 33 – 37 . Although the associations with REM sleep reduction seem strongest for antidepressants, the value of this as an indicator of antidepressant efficacy is limited, especially for novel mechanisms.…”

Section: Discussionmentioning

confidence: 99%

“…In a series of rodent and nonhuman primate studies, TAAR1 agonists have demonstrated wake-promoting effects and have been shown to reduce both rapid eye movement (REM) and non-rapid eye movement (NREM) sleep, likely via modulation of dopaminergic and serotonergic activity in regions associated with sleep state regulation 8 , 13 – 15 . These effects were TAAR1 dependent, as they were not observed in TAAR1 knockout mice, while wake promotion and REM suppression was strongly potentiated in TAAR1 overexpressing animals 14 , 16 .…”

Section: Introductionmentioning

confidence: 99%

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Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

2021

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SEP-363856 is a trace amine-associated receptor 1 (TAAR1) and 5-hydroxytryptamine type 1A (5-HT1A) agonist, currently in Phase 3 clinical trials for the treatment of schizophrenia. Although SEP-363856 activates TAAR1 and 5-HT1A receptors in vitro, an accessible marker of time- and concentration-dependent effects of SEP-363856 in humans is lacking. In rodents, SEP-363856 has been shown to suppress rapid eye movement (REM) sleep. The aim of the current study was to translate the REM sleep effects to humans and determine pharmacokinetic/pharmacodynamic (PK/PD) relationships of SEP-363856 on a measure of brain activity. The effects of SEP-363856 were evaluated in a randomized, double-blind, placebo-controlled, 2-way crossover study of single oral doses (50 and 10 mg) on REM sleep in healthy male subjects (N = 12 at each dose level). Drug concentrations were sampled during sleep to interpolate individual subject’s pharmacokinetic trajectories. SEP-363856 suppressed REM sleep parameters with very large effect sizes (>3) following single doses of 50 mg and plasma concentrations ≥100 ng/mL. Below that effective concentration, the 10 mg dose elicited much smaller effects, increasing only the latency to REM sleep (effect size = 1). The PK/PD relationships demonstrated that REM sleep probability increased as drug concentrations declined below 100 ng/mL over the course of the night. SEP-363856 was generally safe and well tolerated at both doses. The REM sleep-suppressing effects of SEP-363856 provide an accessible marker of brain activity, which can aid in dose selection and help elucidate its therapeutic potential in further clinical trials.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

2021

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“…Consequently, Revel et al (2011) proposed that cotreatment with a TAAR1 agonist might improve therapeutic efficacy of classic antidepressants, providing further support for compounds with dual 5-HT 1A / TAAR1 activity in the treatment of psychosis and mood. Notably, TAAR1 agonists and many antidepressants (especially those with 5-HT 1A activity) exert REM sleep suppression, which is not observed for most D 2 -based antipsychotics (Tribl et al, 2013;Wichniak et al, 2017;Goonawardena et al, 2019). Thus, the robust REM suppression observed with SEP-856 could result from synergistic action on TAAR1 and 5-HT 1A receptors.…”

Section: Discussionmentioning

confidence: 99%

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

Dedic

Jones

Hopkins

et al. 2019

J Pharmacol Exp Ther

150

178

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For the past 50 years, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors. Drug development of non-D 2 compounds, seeking to avoid the limiting side effects of dopamine receptor blockade, has failed to date to yield new medicines for patients. In this work, we report the discovery of SEP-363856 (SEP-856), a novel psychotropic agent with a unique mechanism of action. SEP-856 was discovered in a medicinal chemistry effort utilizing a high throughput, high content, mouse-behavior phenotyping platform, in combination with in vitro screening, aimed at developing non-D 2 (anti-target) compounds that could nevertheless retain efficacy across multiple animal models sensitive to D 2-based pharmacological mechanisms. SEP-856 demonstrated broad efficacy in putative rodent models relating to aspects of schizophrenia, including phencyclidine (PCP)-induced hyperactivity, prepulse inhibition, and PCP-induced deficits in social interaction. In addition to its favorable pharmacokinetic properties, lack of D 2 receptor occupancy, and the absence of catalepsy, SEP-856's broad profile was further highlighted by its robust suppression of rapid eye movement sleep in rats. Although the mechanism of action has not been fully elucidated, in vitro and in vivo pharmacology data as well as slice and in vivo electrophysiology recordings suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on the preclinical data and its unique mechanism of action, SEP-856 is a promising new agent for the treatment of schizophrenia and represents a new pharmacological class expected to lack the side effects stemming from blockade of D 2 signaling. SIGNIFICANCE STATEMENT Since the discovery of chlorpromazine in the 1950s, the clinical efficacy of antipsychotic medications has relied on blockade of dopamine D 2 receptors, which is associated with substantial side effects and little to no efficacy in treating the negative and cognitive symptoms of schizophrenia. In this study, we describe the discovery and pharmacology of SEP-363856, a novel psychotropic agent that does not exert its antipsychotic-like effects through direct interaction with D 2 receptors. Although the mechanism of action has not been fully elucidated, our data suggest that agonism at both trace amine-associated receptor 1 and 5-HT 1A receptors is integral to its efficacy. Based on its unique profile in preclinical species, SEP-363856 represents a promising candidate for the treatment of schizophrenia and potentially other neuropsychiatric disorders. At the time these studies were conducted, all authors were employees of either Sunovion Pharmaceuticals or PsychoGenics. Some authors are inventors on patents related to the subject matter. 1 N.D. and P.G.J. contributed equally to the work.

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“…Histamine, melatonin and taurine are well-known amines associated with sleep induction (76)(77)(78)(79). Both genetic and pharmacological manipulation of TAAR1 alters wakefulness and sleep states (80,81). Even though, our data are restricted to caudoputamen and nucleus accumbens, there is evidence that striatal areas are involved in sleep-wake cycle regulation (82).…”

Section: Taar1 Limits the Changes Of Several Amines But Not Diaminesmentioning

confidence: 76%

TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

Mantas

Vallianatou

Yang

et al. 2021

Biological Psychiatry

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Trace amine-associated receptor 1 agonism promotes wakefulness without impairment of cognition in Cynomolgus macaques

Cited by 17 publications

References 43 publications

Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action

TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

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Trace amine-associated receptor 1 agonism promotes wakefulness without impairment of cognition in Cynomolgus macaques

Cited by 17 publications

References 43 publications

Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

Effect of TAAR1/5-HT1A agonist SEP-363856 on REM sleep in humans

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2Receptor Mechanism of Action

TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

Contact Info

Product

Resources

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SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂Receptor Mechanism of Action