Trace Amines and Their Receptors

Gainetdinov, Raul R.; Hoener, Marius C.; Berry, Mark D.

doi:10.1124/pr.117.015305

Cited by 253 publications

(255 citation statements)

References 646 publications

(1,092 reference statements)

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“…SEP-363856, a Novel, Non-D 2 Psychotropic Agent Gainetdinov et al, 2018;Schwartz et al, 2018). Revel et al (2011) reported the first selective TAAR1 agonist (RO5166017) and demonstrated its inhibitory effects on the firing of dopaminergic and serotonergic neurons.…”

Section: Discussionmentioning

confidence: 99%

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action

Dedic

Jones

Hopkins

et al. 2019

J Pharmacol Exp Ther

124

115

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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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Section: Discussionmentioning

confidence: 99%

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action

Dedic

Jones

Hopkins

et al. 2019

J Pharmacol Exp Ther

124

115

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“…Trace amine‐associated receptors (TAARs) represent a family of G‐protein coupled presynaptic inhibitory receptors activated by elusive amines . TAAR 1 , the most abundant receptor subtype, is widely distributed in many subcortical centers, including the hypothalamus and connected structures (amygdala, limbic system, and centers of the pain matrix) where they modulate the release of DA and NE …”

Section: Tyr Metabolism In Episodic Chmentioning

confidence: 99%

Pathogenesis of Cluster Headache: From Episodic to Chronic Form, the Role of Neurotransmitters and Neuromodulators

D’Andrea¹,

Gucciardi

Perini

et al. 2019

Headache

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Objective.-To describe the role of biochemical anomalies of tyrosine (TYR), tryptophan (TRP), and arginine (ARG) metabolism in patients suffering from episodic and chronic cluster headache (CCH).Background.-The pathogenesis of cluster headache (CH) and the process that transforms the episodic into the chronic form are unknown. However, the accompanying symptoms suggest a dysfunction of the sympathetic system and hypothalamus along with anomalies of metabolism of catecholamines, elusive amines, and nitric oxide (NO) metabolism.Methods.-We describe the results obtained from the last papers published on this issue. The level of metabolites were analyzed by different high-performance liquid chromatography methods.Results.-In both episodic and CH patients, the levels of dopamine and elusive amines are very elevated. The only biochemical difference found in studies between episodic and chronic cluster was that norepinephrine levels were significantly lower in episodic cluster in comparison to control and chronic subjects. In addition, the levels of ARG, homoarginine, and citrulline, precursors of synthesis of NO, were significantly lower in chronic cluster.Conclusions.-All these results suggest that TYR, TRP, and ARG metabolism is abnormal and may constitute a biochemical fingerprint of CH patients. The increased levels of norepinephrine in chronic cluster constitute a possible cause of chronicity of this primary headache. The high levels of tryptamine and its activity on the central serotoninergic system may explain why the length of CH is brief in comparison to migraine and tension-type headache. The low levels of ARG, homoarginine, and citrulline may be the consequence of high circulating levels of α 1 -agonists, such as epinephrine and norepinephrine, and their biochemical interaction with endothelial trace amine-associated receptor 1 that induces activation of NO synthase, resulting in NO synthesis in the circulation, NO release, intense vasodilation, and as a result, the cluster attack.

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“…1,2 Recent studies have also suggested that the regulatory role of the TA system affects neurological disorders such as substance abuse, insomnia, depression, attention deficit hyperactivity disorder, bipolar disorder, schizophrenia and other neuropsychiatric diseases. [3][4][5][6][7][8][9][10] The trace amine-associated receptors (TAARs) were discovered in search of the receptors activated by TAs in the brain. 11,12 The TAAR6 gene (also known as TRAR4 or TA4) is suspected to increase susceptibility to schizophrenia, with evidence of a genetic linkage.…”

Section: Introductionmentioning

confidence: 99%

Accelerated pseudogenization of trace amine‐associated receptor genes in primates

Eyun

2019

Genes Brain and Behavior

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Trace amines (TAs) in the mammalian brain have been investigated for four decades. Trace amine‐associated receptors (TAARs) were discovered during the search for receptors activated by TAs. TAARs are considered a second class of vertebrate olfactory receptors and successfully proliferated in conjunction with adaptation to living on the ground to detect carnivore odors. Thus, therian mammals have a high number of TAAR genes due to rapid species‐specific gene duplications. In primate lineages, however, their genomes have significantly smaller numbers of TAAR genes than do other mammals. To elucidate the evolutionary force driving these patterns, exhaustive data mining of TAAR genes was performed for 13 primate genomes (covering all four infraorders) and two nonprimate euarchontan genomes. This study identified a large number of pseudogenes in many of these primate genomes and thus investigated the pseudogenization event process for the TAAR repertoires. The degeneration of TAARs is likely associated with arboreal inhabitants reducing their exposure to carnivores, and this was accelerated by the change in the nose shape of haplorhines after their divergence from strepsirrhines. Arboreal life may have decreased the reliance on the chemosensing of predators, suggestive of leading to the depauperation of TAAR subfamilies. The evolutionary deterioration of TAARs in primates has been reestablished in recently derived primates due to high selection pressure and probably functional diversity.

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Trace Amines and Their Receptors

Cited by 253 publications

References 646 publications

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action

Pathogenesis of Cluster Headache: From Episodic to Chronic Form, the Role of Neurotransmitters and Neuromodulators

Accelerated pseudogenization of trace amine‐associated receptor genes in primates

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Trace Amines and Their Receptors

Cited by 253 publications

References 646 publications

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D2 Receptor Mechanism of Action

Pathogenesis of Cluster Headache: From Episodic to Chronic Form, the Role of Neurotransmitters and Neuromodulators

Accelerated pseudogenization of trace amine‐associated receptor genes in primates

Contact Info

Product

Resources

About

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action

SEP-363856, a Novel Psychotropic Agent with a Unique, Non-D₂ Receptor Mechanism of Action