Journal Pre-proof

Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for

psychiatry?

Seetal Dodd, André Carvalho, Basant K. Puri, Michael Maes, Chiara

C Bortolasci, Gerwyn Morris, Michael Berk

PII: S0149-7634(20)30585-6
DOI: https://doi.org/10.1016/j.neubiorev.2020.09.028
Reference: NBR 3920

To appear in: Neuroscience and Biobehavioral Reviews

Received Date: 1 May 2020

Revised Date: 31 July 2020
Accepted Date: 25 September 2020

Please cite this article as: Dodd S, Carvalho A, Puri BK, Maes M, Bortolasci CC, Morris G,
Berk M, Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for psychiatry?,
Neuroscience and Biobehavioral Reviews (2020),
doi: https://doi.org/10.1016/j.neubiorev.2020.09.028

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© 2020 Published by Elsevier.

Title: Trace Amine-Associated Receptor 1 (TAAR1): A new drug target for psychiatry?

Authors: Seetal Dodd1,2,3,4, André Carvalho1,5,6, Basant K. Puri7, Michael Maes1, Chiara

C Bortolasci1,8, Gerwyn Morris1 and Michael Berk1,2,3,4

Affiliations:

1. The Institute for Mental and Physical Health and Clinical Translation, Deakin

University, Geelong, Australia

2. Centre for Youth Mental Health, University of Melbourne, Parkville, Australia

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3. Department of Psychiatry, University of Melbourne, Parkville, Australia

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4. University Hospital Geelong, Barwon Health, PO Box 281, Geelong, Victoria, 3220,

Australia
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5. Centre for Addiction and Mental Health (CAMH), Toronto, ON, Canada

6. Department of Psychiatry, Toronto, ON, Canada

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7. C.A.R., Cambridge, UK
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8. Centre for Molecular and Medical Research, School of Medicine, Deakin University,

Geelong, Victoria, Australia

Highlights
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 Trace amine-associated receptors (TAARs) are located in the central nervous system
and peripherally
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 TAARs have a role in homeostasis and rheostasis, and may have a regulatory role in
the monoamine system
 TAAR1 modulators may become an important new drug class for psychiatric
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disorders
 Further research is required to clarify the efficacy, safety and tolerability of TAAR1
modulators
Abstract

There are nine subfamilies of TAARs. They are predominantly intracellular, located in the

central nervous system and peripherally. They have a role in homeostasis and rheostasis, and

also in olfaction. They demonstrate significant cross-talk with the monoamine system and are

involved in the regulation of cAMP signalling and K+ channels. There is evidence to suggest

that TAAR1 may be a promising therapeutic target for the treatment of schizophrenia,

psychosis in Parkinson’s disease, substance use disorders, and the metabolic syndrome and

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obesity. TAAR1 expression may also be a prognostic biomarker for cancers.

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A number of TAAR modulators have been identified, including endogenous ligands and new

chemical entities. Some of these agents have shown efficacy in animal models of addiction
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behaviours, depression and anxiety. Only one agent, SEP-363856, has progressed to

randomised clinical trials in humans; however further, larger studies with SEP-363856 are
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required to clarify its suitability as a new treatment for schizophrenia spectrum disorders.
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SEP-363856 is an agonist of TAAR1 and 5HT1A and it is not clear to what extent its efficacy

can be attributed to TAAR1 rather than to other drug targets. However, current research

suggests that TAAR1 has an important role in human physiology and pathophysiology.
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TAAR1 modulators may become an important new drug class for the management of a wide

array of mental disorders in the future.

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Keywords: Trace Amine-Associated Receptor, SEP-363856, schizophrenia, drug target,

List of Abbreviations

TAAR Trace Amine-Associated Receptor

TAAR gene coding for the trace amine associated receptor

GPCR G protein-coupled receptor

D Dopamine receptor

H Histamine receptor

5HT Serotonin receptor

CNS Central Nervous System

cAMP cyclic adenosine monophosphate

K+ Potassium

SNP single-nucleotide polymorphism

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SNV single-nucleotide variant

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CNV copy-number variant

QSAR quantitative structure–activity relationship

EPPTB
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N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide
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Main text

Background

A recent successful placebo-controlled randomised clinical trial of a trace amine-associated

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receptor 1 (TAAR1) agonist in adults with acute exacerbation of schizophrenia (1), has

catalysed interest in TAAR1 as a novel therapeutic target for mental illness. TAAR1 agonists
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have an efficacy profile that is still being explored. Early data suggests that they have a
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different adverse effect profile compared to other antipsychotic agents, by avoiding the extra-

pyramidal effects associated with dopamine receptor (D2) blockade and weight gain and

metabolic effects associated with histamine (H1) and serotonin 5HT2c binding, although

larger studies are necessary to clarify their safety and tolerability.

Trace amine-associated receptors (TAARs) are G protein-coupled receptors (GPCRs)

expressed in the vertebrate brain. Nine subfamilies of TAAR have been identified across a

range of species (2). TAAR1 is expressed in several brain regions and in the periphery. Other

TAARs are expressed mainly in olfactory regions and to a lesser extent in other brain regions

(3). Endogenous trace amines that bind to TAARs include p-tyramine, β-phenylethylamine,

tryptamine and octopamine, as well as the thyroid hormone metabolite 3-iodothyronamine (4-

6). A range of volatile amines also bind to TAARs and may be associated with their role in

olfactory processes. Several psychotropic agents have been shown to be ligands of TAAR1,

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including amphetamines, ergoline derivatives, bromocriptine and lisuride (7).

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There is considerable evidence linking TAARs to central nervous system (CNS) function and

mammalian behaviour. Knockout TAAR1 mouse models have been studied, where such mice
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showed worse performance in anxiety and working memory tests, increased propensity to

develop alcohol addiction, increased locomotor response to amphetamines and decreased

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stereotypical responses to apomorphine (7, 8). TAAR5 knockout mice showed decreased
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anxiety behaviour in a light-dark box, elevated zero maze and elevated plus maze, and

decreased depressive-like behaviour in the learned helplessness test (3).

Four well known endogenous trace amines can elicit CNS effects. Phenylethylamine may act
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as a post-synaptic neuromodulator of dopamine and noradrenaline neurotransmission (9).

Tryptamine potentiates neural responses to dopamine and causes an increased response to

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noradrenaline in cortical neurones (7). Studied in vitro in rat brain stem, phenylethylamine
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and tryptamine are enhancer substances for impulse-propagation release of catecholamine

and serotonin (9). Octopamine enhances depressant and excitatory responses to noradrenaline

in the rat cerebral cortex (10). 3-Iodothyronamine administration in rodents modulates the

duration of non-REM sleep, produces a pro-learning anti-amnesia effect with novel object

recognition and passive avoidance tests, and regulates food intake in a dose-dependent
manner with increased food intake at higher doses and decreased food intake at lower doses

(7). However, trace amines including thyronamines target TAAR1 and other TAARs, but also

have several other aminergic receptors and non-GPRC targets (11). Consequently, some of

the CNS effects of trace amines may be independent of TAARs.

TAAR genes and their polymorphisms

In lower-order animals trace amines and their receptors appear to have a more prominent role

compared to higher-order species, although both monoamine and trace amine systems exist in

invertebrate and simple chordate species. An early mammalian ancestor is thought to have

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had nine distinct TAAR genes (12), corresponding to the nine TAAR subfamilies. The gene

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TAAR1 has been evolutionarily more stable than other TAAR genes, although it demonstrates

sequence divergence and varying pharmacological profiles across species (12). Genes TAAR1
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and TAAR5 are the best conserved across primate species (12), and the two corresponding

receptors are the best described in relation to pathophysiological processes.

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Human TAAR genes are clustered into a small region of chromosome 6q23 that has been
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identified through linkage analysis as a region associated with schizophrenia and affective

disorder (2). There are many variations of TAAR genes including single-nucleotide

polymorphisms (SNPs), single-nucleotide variants (SNVs) and copy-number variants

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(CNVs). Association studies have linked schizophrenia with variations in TAAR6, TAAR2 and

TAAR5, and bipolar disorder with TAAR1, TAAR5 and TAAR6. An exome sequencing study
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linked TAAR1 with schizophrenia (2).

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A search of TAAR1 in the SNP database, https://www.ncbi.nlm.nih.gov/snp, yielded 4,870

results, suggesting that there are a large number of polymorphisms of the TAAR1 gene. A

study of the common variant TAAR1 synonymous SNP V288V, a polymorphism that

demonstrates a 40% increase in TAAR1 expression in vitro, investigated the relation between

V288V and symptoms in methamphetamine users. Having at least one copy of V288V was
associated with 1.55 times the mean response for drug craving in active methamphetamine

users and 1.77 times the mean response for drug craving in methamphetamine users who

were in remission (13). Elsewhere, single-nucleotide variants of TAAR1 were detected with

greater frequency in a cohort of obese and overweight patients with impaired insulin

secretion compared to the general population. The association between these single-

nucleotide variants and weight regulation and glucose homeostasis remains to be investigated

(14). Similarly, thirteen missense variants of TAAR1 were found at greater frequency in a

cohort of patients with major mental disorders compared to health controls (15).

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Methamphetamine consumption is increased in TAAR1 knockout mouse models (16, 17), and

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this finding was extended to show that mice with a TAAR1 polymorphism also had increased

methamphetamine consumption and that SNPs in human TAAR1 also could also result in sub-

functional and non-functional receptors (16).

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TAAR as a putative target for psychotherapeutic agents
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TAARs are of interest as therapeutic targets for addictive disorders, schizophrenia and the

metabolic syndrome. Variants of TAAR1 are associated with impaired glycaemic control and

body weight regulation (14). The role of TAARs in normal human function is not fully
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understood, and lags significantly behind the numerous studies that have been conducted in

rodents and other vertebrates. In rodents, TAARs have olfactory and non-olfactory roles.
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TAAR1 is absent in the rodent olfactory system and is substantially expressed in the gut, with
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a role in food absorption and glucose metabolism (7).

Pertinent to a posited mechanism of action for the treatment of schizophrenia, cross-talk

between TAAR and monoamine systems has been demonstrated. Evidence includes changes

in firing rates of rat dopaminergic and serotonergic neurones in response to TAAR1 agonist

administration (7, 18, 19). There is some evidence linking trace amines with modulation of
K+ channels and further evidence suggesting that TAAR1 may modulate electrophysiology

either through monoamine autoreceptors or transporters (7). A complex relationship has been

described where TAAR1 is implicated in rheostasis, regulating the activity of dopaminergic

neurones (20). TAAR1 agonists have been reported both to increase and decrease dopamine

release in the nucleus accumbens and other brain regions and TAAR1 antagonists were

demonstrated to provoke increased agonist affinity to D2 (7). Furthermore, D2 receptor

ligands have been shown to modulate TAAR1 activity in TAAR1 expressing cells (21),

although this may be consequential to alterations in trace amine concentrations.

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There is also evidence from a study of methamphetamine users of modulation of

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glutamatergic transmission in the prefrontal cortex with TAAR1 activation.

Methamphetamine causes the overexpression of TAAR1 in astrocytes, leading to increases of

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cyclic adenosine monophosphate (cAMP) levels which in turn decrease the clearance of

glutamate (22).
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TAAR1 is predominantly intracellularly located, rather than located on the cell surface
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membrane. Interestingly, it is co-localised with the dopamine transported in some

dopaminergic cells of the substantia nigra and co-expressed with the noradrenaline

transporter of adrenergic cells of the locus coeruleus of rhesus monkeys, and co-localised
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with the serotonin transporter of serotonergic neurones of murine dorsal raphe nucleus (23).

The localisation of TAAR1 supports the hypothesis that TAAR1 influences the monoamine
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system through downstream effects.

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TAAR and pathology outside the CNS

TAAR1 has been identified as a regulator of gastrointestinal and pancreatic islet hormone

secretion and may be a potential target for novel type 2 diabetes mellitus and obesity drugs

(24). TAAR1 is expressed in the gut and may have a role in inflammatory bowel diseases,

and comorbid of neuropsychiatric disorders and gastrointestinal disorders (25). TAAR1 has a
role in immune system regulation and immune cell activation and is of interest in oncology.

For example, bone-marrow-derived macrophages may express TAAR1 and stimulation by

tyramine increases production of pro-inflammatory cytokines (26) Lymphocyte activation

following PHA-stimulation is accompanied by increased TAAR1 expression and signalling,

indicating that TAAR1 may play a role in modulation of immune-inflammatory responses

(27) Also, methamphetamine administration may activate TAAR1 thereby regulating

interleukin-2 production and cAMP activation (28). It has been postulated that TAAR1

expression may have a role as a prognostic marker of cancer progression (29). Sites where

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TAAR1 are located are shown in figure 1.

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TAAR modulating agents

Although useful as research tools, endogenous trace amines are not suitable drug candidates.
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In vivo, they are rapidly cleared. The discovery of novel TAAR modulating agents

commenced in the decade following the discovery of TAARs.

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High-throughput screening was conducted on a library of approximately 788,000 compounds
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using a functional cAMP assay of chimeric rat/human TAAR1 that could identify agonists

and antagonists, with the positive hits then tested in mouse TAAR1 for dose-response

determination. Benzanilides and nicotinanilides were detected as the classes of compounds

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that most strongly modulated TAAR1 (30). Some of these compounds and their analogues,

usually referenced by F. Hoffman-La Roche identification numbers (RO0000000), have been

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studied further both as basic research tools and as potential drug candidates. However, none
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of these compounds has progressed down the drug discovery pipeline. Roche currently have

no registered clinical trials of agents that are publicly declared TAAR modulator drugs,

however, not all Roche agents currently being trialled have a publicly disclosed mechanism

of action (e.g. RO6889450, NCT03669640).

Many of these Roche TAAR1 modulators have been mentioned in publicly available

literature, often simply as a description of their molecular structure (30). However, some

compounds have been investigated further and made available to academic researchers; they

have primarily been of interest to researchers of substance abuse in animal models, and there

has been some enthusiasm that they may be potential therapeutic agents. The full agonists

RO5166017 and RO5256390 as well as partial agonists RO5263397 and RO5203648

successfully reduced measures of abuse behaviour in rodent models of cocaine abuse (31,

32). A study of TAAR1 partial agonist RO5203648 demonstrated antipsychotic- and

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antidepressant-like activities as well as potential anxiolytic-like properties in rodent and

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primate animal models (33).

Further investigations of RO5263397 demonstrated response in the forced swim test, a rodent
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model of depression-like behaviours (34). These positive test behaviours were blocked by

pre-treatment with a dopamine D1 or a glutamate AMPA receptor antagonist, but only

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partially blocked by a serotonin 5HT1A receptor antagonist. TAAR1 directly interacts with D2
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but not D1 receptors (35). It was postulated that TAAR1 has a downstream effect on cortical

D1 receptors linked to antidepressant activity (34). A variable dose study of RO5263397 in 49

healthy male subjects aged 18–45 years, to investigate safety, tolerability, pharmacokinetics,
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and pharmacodynamics after oral administration, identified one individual subject who

showed 136-fold higher exposure and 22-fold higher peak concentration versus all other
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subjects receiving the same 10-mg dose. Further investigations identified two further
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individual, all three of African origin, who were poor metabolisers of RO5263397. Clearance

of RO5263397 is glucuronidation by the hepatic enzymes UGT1A4 and UGT2B10. Poor

metaboliser phenotype for UGT2B10 is common in people of African origin (45%), of

moderate frequency in Asians (8%) and uncommon in Caucasians (<1%) (36).

Another approach to TAAR drug development has been through efforts to develop and

characterise analogues of endogenous trace amines (37). There have been efforts to develop

analogues of 3-iodothryonamine as a potential anti-obesity drug, perhaps also with benefit for

the treatment of metabolic and neurodegenerative disorders (38). These efforts have

encountered difficulties of rapid clearance through multiple metabolic pathways and lack of

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selectivity; however, work is ongoing.

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In addition to other techniques, computational tools such as modelling of human and mouse

TAAR1 have been used to investigate species-specific variations and quantitative structure–
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activity relationship (QSAR) models have been used to predict biological activity (39).

A recent patent review from 2010 to 2019 identified 23 published patents of TAAR1
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modulators; 18 by F. Hoffmann-La Roche AG, two by Purdue Pharma LP and three by
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named individuals (39). A TAAR1 modulator developed by Sunovion Pharmaceuticals, SEP-

363856, is the novel agent furthest progressed along the drug discovery pipeline.

SEP-363856 as a novel therapeutic agent for schizophrenia

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Incomplete data describing the pharmacological profile of SEP-363856 are available in the

public domain. SEP-363856 is a TAAR1 and 5HT1A agonist without significant affinity for
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5HT2A or D2 (40). An in vitro study suggested that SEP-363856 has a high half-maximal
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effective concentration (EC50), a measure of agonist potency, for TAAR1 (0.14 M) and

5HT1A (2.3 M) but also for 5HT1D (0.262 M), 5HT7 (6.7 M), D2L (long form) (10.44 M

and 8.02 M, using cAMP and arrestin recruitment methods, respectively), and EC50 > 10

M for 5HT1D, 5HT2A, 5HT2c and adrenergic receptor 2A. No significant antagonist potency

was demonstrated with inhibitor concentration IC50 testing (41). A positron emission
tomography study of non-human primates showed that SEP-363856 occupancy of D2 was not

significant (41).

Using a whole cell patch-clamp technique, SEP-363856 inhibited firing of mouse dorsal

raphe nucleus (DRN) neurons. These inhibitory effects were reversable by administering the

5-HT1A antagonist WAY-100635, demonstrating involvement of 5HT1A receptors (42).

Furthermore, SEP-363856 inhibited neuronal firing and decreases excitability in the ventral

tegmental area (VTA), with the inhibitory effect of SEP-856 was blocked by the TAAR1

antagonist EPPTB (RO-5212773) in some but not all VTA neurons. These inhibitory effects

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of SEP-856 persisted in the presence of the 5-HT1A antagonist WAY-100635 (42).

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Pharmacokinetic parameters are reported for mouse, rat and rhesus monkey, at 5 and 10

mg/kg doses with oral and intravenous administration (41), suggesting that the rapid
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clearance observed for endogenous TAAR ligands is not a problem for SEP-363856. Human

pharmacokinetic parameters are not available in the public domain; however, once daily
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dosing has been used in clinical trials.
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A randomised controlled trial (RCT) compared SEP-363856 to placebo in adults (n = 245)

with an acute exacerbation of schizophrenia. Following a 14-day washout period in which all
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psychotropic medications were discontinued, participants were treated with SEP-363856 (50

mg/day or 75 mg/day) or placebo for four weeks, with an optional 26-week open-labelled
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extension study. At week four, SEP-363856 was superior to placebo in reduction in PANSS
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total score (p = 0.001), with a mean change of -17.2 from a baseline score of 101.4 in the

SEP-363856 group and a mean change of -9.7 from a baseline score of 99.7 in the placebo

group. Two serious adverse events during the four-week trial were deemed unlikely to be

related to the study medication (one was in a participant assigned to placebo and the other

had pre-existing cardiovascular disease). No obvious safety or tolerability concerns emerged

during this phase of the trial. The extension study recruited 156 participants. During the 26-

week open-label treatment period, a further -17.1 point change of the PANSS total score was

observed for the 77 participants who had initially been randomised to SEP-363856 and a -

27.9 point change of the PANSS total score was observed for the 79 participants who had

initially been randomised to placebo (1).

A search for clinical trials in the clinicaltrials.gov database for SEP-363856 (20th April 2020)

yielded 13 results. These included 12 trials in schizophrenia, five of which are completed and

included the efficacy study mentioned above, where the double-blind and extension studies

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were registered separately and three unpublished safety and tolerability studies. Two large,

multisite efficacy studies in schizophrenia are currently active. A small trial in Parkinson’s

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disease psychosis is also registered. Notwithstanding promising preclinical data in mood
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disorders and addictions, these indications remain unexplored.

Conclusion
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TAARs are important receptors located in the brain and periphery. They are predominantly
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intracellular and have a role in homeostasis and rheostasis. They demonstrate significant

cross-talk with the monoamine system and are involved in the regulation of cAMP and K+

channels. There is evidence to suggest that TAAR1 may be a promising therapeutic target for
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the treatment of schizophrenia, psychosis in Parkinson’s disease, substance abuse, and

metabolic syndrome and obesity. TAAR1 expression may be a prognostic marker for cancers.
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Nevertheless, since schizophrenia, Parkinson’s disease, metabolic syndrome, obesity and

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mood disorders are characterized by immune-inflammatory responses, it is important that the

immune effects of TAAR1 agonists and antagonists should first be established.

A number of TAAR modulators have been identified, including endogenous ligands and new

chemical entities. Only one agent, SEP-363856, has progressed to RCTs in humans, however

further, larger studies with SEP-363856 are required to clarify its suitability as a new
treatment for schizophrenia and related disorders. SEP-363856 is an agonist of TAAR1 and

5HT1A and it is not clear to what extent its efficacy can be attributed to TAAR1 rather than to

other drug targets. However, current research suggests that TAAR1 has an important role in

human physiology and pathophysiology. TAAR1 modulators may become an important new

drug class in the future.

Acknowledgements

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MB is supported by a National Health and Medical Research Council (NHMRC) Senior

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Principal Research Fellowship (APP1059660 and APP1156072)

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Figure 1: Diagram showing sites where TAAR1 are located in humans.

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