Putative TAAR5 agonist alpha-NETA affects event-related potentials in oddball paradigm in awake mice

Aa, Aleksandrov; Knyazeva, Veronika M.; Volnova, Anna; Dmitrieva, E. S.; Polyakova, N. V.

doi:10.1016/j.brainresbull.2020.03.005

Cited by 6 publications

(6 citation statements)

References 62 publications

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“…These findings are not sufficient to fully appreciate TAAR5's functional significance as well as its potential involvement in the pathogenesis of neuropsychological diseases. At the same time, the evidence of the presence of TAAR5 in the human brain structures enables the translation of accumulating knowledge about the functional role of this receptor [6,[19][20][21][22]43] from model animals to humans.…”

Section: Source Of Biasmentioning

confidence: 99%

“…Opposite effects were demonstrated in animals, treated with putative TAAR5 agonist α-NETA. This substance disrupts sensory information processing and alters brain electrophysiological activity in mice in a manner consistent with psychotic states [19][20][21][22]. Most importantly, prominent expression of TAAR5 was observed not only in the olfactory bulb but also in numerous limbic brain regions receiving olfactory input, such as the anterior olfactory nucleus, the olfactory tubercle, the orbitofrontal cortex, the amygdala, the hippocampus, the piriform cortex, the entorhinal cortex, the nucleus accumbens, and the thalamic and hypothalamic nuclei.…”

Section: Introductionmentioning

confidence: 99%

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Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis

Vaganova

Murtazina

Shemyakova

et al. 2021

IJMS

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Trace amine-associated receptors (TAAR) recognize organic compounds, including primary, secondary, and tertiary amines. The TAAR5 receptor is known to be involved in the olfactory sensing of innate socially relevant odors encoded by volatile amines. However, emerging data point to the involvement of TAAR5 in brain functions, particularly in the emotional behaviors mediated by the limbic system which suggests its potential contribution to the pathogenesis of neuropsychiatric diseases. TAAR5 expression was explored in datasets available in the Gene Expression Omnibus, Allen Brain Atlas, and Human Protein Atlas databases. Transcriptomic data demonstrate ubiquitous low TAAR5 expression in the cortical and limbic brain areas, the amygdala and the hippocampus, the nucleus accumbens, the thalamus, the hypothalamus, the basal ganglia, the cerebellum, the substantia nigra, and the white matter. Altered TAAR5 expression is identified in Down syndrome, major depressive disorder, or HIV-associated encephalitis. Taken together, these data indicate that TAAR5 in humans is expressed not only in the olfactory system but also in certain brain structures, including the limbic regions receiving olfactory input and involved in critical brain functions. Thus, TAAR5 can potentially be involved in the pathogenesis of brain disorders and represents a valuable novel target for neuropsychopharmacology.

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Section: Source Of Biasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis

Vaganova

Murtazina

Shemyakova

et al. 2021

IJMS

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“…α-NETA, an inhibitor of acetyl-cholinesterase, potently activates TAAR5, and displays interesting in vivo properties in mice and rats, inducing psychotic-like states and influencing cortical parameters related to cognitive functions [25,26,[34][35][36].…”

Section: Discussionmentioning

confidence: 99%

“…Although with lower potencies, two other tertiary amines activate TAAR5, namely N-N-dimethylethylamine and N-methylpiperidine [ 5 ]. α-NETA, an inhibitor of acetyl-cholinesterase, potently activates TAAR5, and displays interesting in vivo properties in mice and rats, inducing psychotic-like states and influencing cortical parameters related to cognitive functions [ 25 , 26 , 34 , 35 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

Bon

Chern

Cichero

et al. 2022

IJMS

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Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to further develop more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.

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“…Although with lower potencies, other two tertiary amines activate TAAR5, namely N-N-dimethylethylamine and N-methylpiperidine [5]. α-NETA, an inhibitor of acetyl-cholinesterase, potently activates TAAR5, and displays interesting in vivo properties in mice and rats, inducing psychotic-like states and influencing cortical parameters related to cognitive functions [25,26,[34][35][36].…”

Section: Discussionmentioning

confidence: 99%

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

Bon¹,

Chern²,

Cichero³

et al. 2022

Preprint

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Trace amine-associated receptor 5 (TAAR5) is a G protein-coupled receptor that belongs to the TAARs family (TAAR1-TAAR9). TAAR5 is expressed in the olfactory epithelium and is responsible for sensing 3-methylamine (TMA). However, recent studies showed that TAAR5 is also expressed in the limbic brain regions and is involved in the regulation of emotional behaviour and adult neurogenesis, suggesting that TAAR5 antagonism may represent a novel therapeutic strategy for anxiety and depression. We used the AtomNet® model, the first deep learning neural network for structure-based drug discovery, to identify putative TAAR5 ligands and tested them in an in vitro BRET assay. We found two mTAAR5 antagonists with low to submicromolar activity that are able to inhibit the cAMP production induced by TMA. Moreover, these two compounds also inhibited the mTAAR5 downstream signalling, such as the phosphorylation of CREB and ERK. These two hits exhibit drug-like properties and could be used to develop further more potent TAAR5 ligands with putative anxiolytic and antidepressant activity.

show abstract

Putative TAAR5 agonist alpha-NETA affects event-related potentials in oddball paradigm in awake mice

Cited by 6 publications

References 62 publications

Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis

Pattern of TAAR5 Expression in the Human Brain Based on Transcriptome Datasets Analysis

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

Discovery of Novel Trace Amine-Associated Receptor 5 (TAAR5) Antagonists Using a Deep Convolutional Neural Network

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