The Experts below are selected from a list of 2532 Experts worldwide ranked by ideXlab platform
Raul R. Gainetdinov - One of the best experts on this subject based on the ideXlab platform.
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Trace Amine-Associated Receptor 1 Agonist Modulates Mismatch Negativity-Like Responses in Mice
Frontiers Media S.A., 2019Co-Authors: Aleksande A. Aleksandrov, Veronika M. Knyazeva, Anna . Volnova, Elena S. Dmitrieva, Nadezhda V. Polyakova, Raul R. GainetdinovAbstract:The Trace Amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor widely expressed in the mammalian brain, particularly in limbic system and monoAminergic areas. It has proven to be an important modulator of dopAminergic, serotoninergic, and glutamatergic neurotransmission and is considered to be a potential useful target for the pharmacotherapy of neuropsychiatric disorders, including schizophrenia. One of the promising schizophrenia endophenotypes is a deficit in neurocognitive abilities manifested as mismatch negativity (MMN) deficit. This study exAmines the effect of TAAR1 partial agonist RO5263397 on the MMN-like response in freely moving C57BL/6 mice. Event-related potentials (ERPs) were recorded from awake mice in the oddball paradigm before and after RO5263397 administration. The RO5263397 (but not saline) administration increased the N40 amplitude in response to deviant stimuli. That provided the MMN-like difference at the 36–44 ms interval after the injection. The pitch deviance-elicited changes before the injection and in the control paradigm were established for the P68 component. After TAAR1 agonist administration the P68 amplitude in response both to standard and deviant stimuli was increased. These results suggest that the MMN-like response in mice may be modulated through TAAR1-dependent processes (possibly acting through the direct or indirect glutamate NMDA receptor modulation), indicating the TAAR1 agonists potential antipsychotic and pro-cognitive activity
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activation of Trace Amine associated receptor 1 attenuates schedule induced polydipsia in rats
Neuropharmacology, 2019Co-Authors: I. Sukhanov, Marius C. Hoener, Raul R. Gainetdinov, Antonina Dolgorukova, Artem Dorotenko, Anton BespalovAbstract:Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopAminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.
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Trace Amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases.
Expert opinion on therapeutic targets, 2018Co-Authors: Michael D. Schwartz, Riccardo Zucchi, Stefano Espinoza, Juan J. Canales, I. Sukhanov, Raul R. GainetdinovAbstract:ABSTRACTIntroduction: The Trace Amines, endogenous Amines closely related to the biogenic Amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a Trace Amine-sensitive G protein-coupled receptor, Trace Amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of Trace Amine signaling.Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronAmine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopAminergic signaling is likely to underlie many of its CNS effects. How...
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Trace Amine associated receptor 1 modulates the locomotor and sensitization effects of nicotine
Frontiers in Pharmacology, 2018Co-Authors: I. Sukhanov, Raul R. Gainetdinov, Mariia Dorofeikova, Antonina Dolgorukova, A DorotenkoAbstract:Trace Amine-associated receptor 1 (TAAR1) has emerged as a promising target for addiction treatments because it affects dopAmine transmission in the mesolimbic pathway. TAAR1 is involved in the effects of addictive drugs, such as amphetAmines, cocaine and ethanol, but the impact of TAAR1 on the effects of nicotine, the psychoactive drug responsible for the development and maintenance of tobacco smoking, has not yet been studied. This study was performed to investigate the possible modulatory action of TAAR1 on the effects of nicotine on locomotor behaviors in rats and mice. Pretreatment with the TAAR1 agonist RO5263397 dose-dependently decreased nicotine-induced hyperlocomotion in rats habituated to locomotor boxes, prevented the development of nicotine sensitization and blocked hypermotility in nicotine-sensitized rats at the highest tested dose (10 mg/kg). The lack of TAAR1 failed to affect the effects of nicotine on the locomotion of mutant mice. Based on the results of the present study, TAAR1 activation attenuates the locomotion-stimulating effects of nicotine on rats. These results further support the previously proposed hypothesis that TAAR1 is a promising target for the prevention and treatment of drug addiction. Further studies aimed at analyzing the effects of TAAR1 agonists on animal models of nicotine addiction are warranted.
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Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397
Frontiers Media S.A., 2018Co-Authors: Stefano Espinoza, Raul R. Gainetdinov, Tatyana D. Sotnikova, Damiana Leo, Mohammed Shahid, Tiina M. KääriäinenAbstract:Trace Amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating inTracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated the role of TAAR1 in the regulation of dopAminergic system and its importance in physiological processes such as locomotion, control of emotional states and cognition. In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and characterized its pharmacology in vitro in HEK293 cells and its effects in vivo in tests assessing potential antidepressant and antipsychotic actions. We found that RO5263397 not only increases cAMP levels at very low concentrations but also can induce the phosphorylation of ERK and CREB in a concentration- and time-dependent manner. Like other TAAR1 agonists, RO5263397 potently suppressed high dopAmine-dependent hyperactivity in mice lacking the dopAmine transporter. Moreover, RO5263397 produced a strong antidepressant-like effect in the forced swim test comparable to fluoxetine. Furthermore, the antidepressant-like activity was blocked by pretreatment with SCH23390 (dopAmine D1 receptor antagonist) or NBQX (glutamate AMPA receptor antagonist) but only in part by WAY100635 (serotonin 5HT1A receptor antagonist). In conclusion, our study confirms some previous in vitro and in vivo findings in relation to the pharmacological effects of RO5263397 but more importantly provides new insight on inTracellular signaling pathway and other neurotransmitter receptors modulated by TAAR1 receptor activation
Gregory M. Miller - One of the best experts on this subject based on the ideXlab platform.
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Actions of Trace Amines in the Brain-Gut-Microbiome Axis via Trace Amine-Associated Receptor-1 (TAAR1)
Cellular and Molecular Neurobiology, 2020Co-Authors: Katlynn Bugda Gwilt, Dulce Pamela González, Neva Olliffe, Haley Oller, Rachel Hoffing, Marissa Puzan, Sahar El Aidy, Gregory M. MillerAbstract:Trace Amines and their primary receptor, Trace Amine-Associated Receptor-1 (TAAR1) are widely studied for their involvement in the pathogenesis of neuropsychiatric disorders despite being found in the gastrointestinal tract at physiological levels. With the emergence of the “brain-gut-microbiome axis,” we take the opportunity to review what is known about Trace Amines in the brain, the defined sources of Trace Amines in the gut, and emerging understandings on the levels of Trace Amines in various gastrointestinal disorders. Similarly, we discuss localization of TAAR1 expression in the gut, novel findings that TAAR1 may be implicated in inflammatory bowel diseases, and the reported comorbidities of neuropsychiatric disorders and gastrointestinal disorders. With the emergence of TAAR1 specific compounds as next-generation therapeutics for schizophrenia (Roche) and Parkinson’s related psychoses (Sunovion), we hypothesize a therapeutic benefit of these compounds in clinical trials in the brain-gut-microbiome axis, as well as a potential for thoughtful manipulation of the brain-gut-microbiome axis to modulate symptoms of neuropsychiatric disease.
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Trace Amine associated receptor 1 modulates behavioral effects of ethanol
Substance Abuse: Research and Treatment, 2013Co-Authors: Laurie J Lynch, Eric J. Vallender, Katherine A Sullivan, James K Rowlett, Donna M Platt, Gregory M. MillerAbstract:Background: Few treatment options for alcohol use disorders (AUDs) exist and more are critically needed. Here, we assessed whether Trace Amine associated receptor 1 (TAAR1), a modulator of brain monoAmine systems, is involved in the behavioral and reinforcement-related effects of ethanol and whether it could potentially serve as a therapeutic target. Methods: Wild-type (WT) and TAAR1 knockout (KO) mice (75% C57J/BL6 and 25% 129S1/Sv background) were compared in tests of ethanol consumption (two-bottle choice [TBC]), motor impairment (loss of righting reflex, [LORR], locomotor activity) and ethanol clearance (blood ethanol level [BEL]). Results: As compared with WT mice, KO mice displayed (1) significantly greater preference for and consumption of ethanol in a TBC paradigm (3%–11% vol/vol escalating over 10 weeks), with no significant difference observed in TBC with sucrose (1%–3%); (2) significantly greater sedative-like effects of acute ethanol (2.0 or 2.5 g/kg, intraperitoneal [i.p.]) manifested as LORR observed at a lower dose and for longer time, with similar BELs and rates of ethanol clearance; and (3) lower cumulative locomotor activity over 60 minutes in response to an acute ethanol challenge (1.0–2.5 g/kg, i.p.). Conclusions: The present findings are the first to implicate TAAR1 in the behavioral and reinforcement-related effects of ethanol and raise the question of whether specific drugs that target TAAR1 could potentially reduce alcohol consumption in humans with AUDs.
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Trace Amine Associated Receptor 1 Signaling in Activated Lymphocytes
Journal of Neuroimmune Pharmacology, 2012Co-Authors: Michael W. Panas, Marius C. Hoener, Helen N Panas, Eric J. Vallender, Gregory M. MillerAbstract:Although most research to date on Trace Amine Associated Receptor 1 (TAAR1) has focused on its role in the brain, it has been recognized since its discovery in 2001 that TAAR1 mRNA is expressed in peripheral tissues as well, suggesting that this receptor may play a role in non-neurological pathways. This study reports TAAR1 expression, signaling and functionality in rhesus monkey lymphocytes. We detected a high level of TAAR1 protein in immortalized rhesus monkey B cell lines and a significant upregulation of TAAR1 protein expression in rhesus monkey lymphocytes following PHA treatment. Through screening a wide range of signaling pathways for their upregulation following TAAR1 activation by its potent agonist methamphetAmine, we identified two transcription factors, CREB and NFAT, which are commonly associated with immune activation. Furthermore, we observed a TAAR1-dependent phosphorylation of PKA and PKC following treatment with methamphetAmine in transfected HEK293 cells, immortalized rhesus monkey B cells and PHA-activated rhesus monkey lymphocytes. Accordingly, the high levels of TAAR1 that we observed on lymphocytes are inducible and fully functional, capable of transmitting a signal likely via PKA and PKC activation following ligand binding. More importantly, an increase in TAAR1 receptor expression is concomitant with lymphocyte immune activation, suggesting a possible role for TAAR1 in the generation or regulation of an immune response. TAAR1 is emerging as a potential therapeutic target, with regard to its ability to modulate brain monoAmines. The current data raises the possibility that TAAR1-targeted drugs may also alter immune function.
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Trace Amine associated receptor 1 is a stereoselective binding site for compounds in the amphetAmine class
Bioorganic & Medicinal Chemistry, 2011Co-Authors: Anita H Lewin, Gregory M. Miller, Brian P GilmourAbstract:The demonstrated ability of amphetAmine to functionally activate the rat Trace Amine associated receptor 1 (rTAAR1) and the subsequent reports of amphetAmine activation of TAAR1 in rhesus monkey mouse, human, and human-rat chimeric TAAR1-expressing cell lines has led to speculation as to the role of this receptor in the central nervous system (CNS) responses associated with amphetAmine and its analogs. The agonist potencies of ten pairs of enantiomeric amphetAmines, including several with known CNS activity, at primate TAAR1 stably expressed in RD-HGA16 cells, robustly indicate the S-configuration to be associated with higher potency. Moreover, the rank order of potency to activate TAAR1 parallels the stimulant action reported by humans for the specific amphetAmines. Taken together, these data suggest that TAAR1 is a stereoselective binding site for amphetAmine and that activation of TAAR1 is involved in the modulation of the stimulant properties of amphetAmine and its congeners. In addition, the observed parallel between hTAAR1 and rhTAAR1 responses supports the rhesus monkey as a highly translational model for developing novel TAAR1-directed compounds as therapeutics for amphetAmine-related addictions.
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Behavioral effects of clozapine: Involvement of Trace Amine pathways in C. elegans and M. musculus
Brain research, 2011Co-Authors: Rakesh Karmacharya, Gregory M. Miller, Spencer K. Lynn, Sarah E. Demarco, Angelica Ortiz, Xin Wang, Miriam Lundy, Zhihua Xie, Bruce M. Cohen, Edgar A. ButtnerAbstract:Clozapine is an antipsychotic medication with superior efficacy in treatment refractory schizophrenia. The molecular basis of clozapine's therapeutic profile is not well understood. We studied behavioral effects of clozapine in Caenorhabditis elegans to identify novel pathways that modulate clozapine's biological effects. Clozapine stimulated egg laying in C. elegans in a dose-dependent manner. This effect was clozapine-specific, as it was not observed with exposure to a typical antipsychotic, haloperidol or an atypical antipsychotic, olanzapine. A candidate gene screen of biogenic Amine neurotransmitter systems identified signaling pathways that mediate this clozapine-specific effect on egg laying. Specifically, we found that clozapine-induced increase in egg laying requires tyrAmine biosynthesis. To test the implications of this finding across species, we explored whether Trace Amine systems modulate clozapine's behavioral effects in mammals by studying Trace Amine-associated receptor 1 (TAAR1) knockout mice. Clozapine increased prepulse inhibition (PPI) in wild-type mice. This increase in PPI was abrogated in TAAR1 knockout mice, implicating TAAR1 in clozapine-induced PPI enhancement. In transfected mammalian cell lines, we found no TAAR activation by antipsychotics, suggesting that modulation of Trace Amine signaling in mice does not occur directly at the receptor itself. In summary, we report a heretofore-unknown role for Trace Amine systems in clozapine-mediated effects across two species: C. elegans and mice.
Stefano Espinoza - One of the best experts on this subject based on the ideXlab platform.
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Trace Amine-associated receptor 1: a multimodal therapeutic target for neuropsychiatric diseases.
Expert opinion on therapeutic targets, 2018Co-Authors: Michael D. Schwartz, Riccardo Zucchi, Stefano Espinoza, Juan J. Canales, I. Sukhanov, Raul R. GainetdinovAbstract:ABSTRACTIntroduction: The Trace Amines, endogenous Amines closely related to the biogenic Amine neurotransmitters, have been known to exert physiological and neurological effects for decades. The recent identification of a Trace Amine-sensitive G protein-coupled receptor, Trace Amine-associated receptor 1 (TAAR1), and subsequent development of TAAR1-selective small-molecule ligands, has renewed research into the therapeutic possibilities of Trace Amine signaling.Areas covered: Recent efforts in elucidating the neuropharmacology of TAAR1, particularly in neuropsychiatric and neurodegenerative disease, addiction, and regulation of arousal state, will be discussed. Focused application of TAAR1 mutants, synthetic TAAR1 ligands, and endogenous biomolecules such as 3-iodothyronAmine (T1AM) has yielded a basic functional portrait for TAAR1, despite a complex biochemistry and pharmacology. The close functional relationship between TAAR1 and dopAminergic signaling is likely to underlie many of its CNS effects. How...
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Biochemical and Functional Characterization of the Trace Amine-Associated Receptor 1 (TAAR1) Agonist RO5263397
Frontiers Media S.A., 2018Co-Authors: Stefano Espinoza, Raul R. Gainetdinov, Tatyana D. Sotnikova, Damiana Leo, Mohammed Shahid, Tiina M. KääriäinenAbstract:Trace Amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor, which signals through elevating inTracellular cAMP levels, and expressed in most vertebrates, including rodents and humans. In recent years, several lines of evidence indicated the role of TAAR1 in the regulation of dopAminergic system and its importance in physiological processes such as locomotion, control of emotional states and cognition. In our study, we used RO5263397, a selective TAAR1 agonist, as a tool and characterized its pharmacology in vitro in HEK293 cells and its effects in vivo in tests assessing potential antidepressant and antipsychotic actions. We found that RO5263397 not only increases cAMP levels at very low concentrations but also can induce the phosphorylation of ERK and CREB in a concentration- and time-dependent manner. Like other TAAR1 agonists, RO5263397 potently suppressed high dopAmine-dependent hyperactivity in mice lacking the dopAmine transporter. Moreover, RO5263397 produced a strong antidepressant-like effect in the forced swim test comparable to fluoxetine. Furthermore, the antidepressant-like activity was blocked by pretreatment with SCH23390 (dopAmine D1 receptor antagonist) or NBQX (glutamate AMPA receptor antagonist) but only in part by WAY100635 (serotonin 5HT1A receptor antagonist). In conclusion, our study confirms some previous in vitro and in vivo findings in relation to the pharmacological effects of RO5263397 but more importantly provides new insight on inTracellular signaling pathway and other neurotransmitter receptors modulated by TAAR1 receptor activation
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Hit-to-Lead Optimization of Mouse Trace Amine Associated Receptor 1 (mTAAR1) Agonists with a Diphenylmethane-Scaffold: Design, Synthesis, and Biological Study.
Journal of Medicinal Chemistry, 2016Co-Authors: Grazia Chiellini, Giulia Nesi, Simona Sestito, Sara Chiarugi, Massimiliano Runfola, Stefano Espinoza, Martina Sabatini, Lorenza Bellusci, Annunziatina Laurino, Elena CicheroAbstract:The Trace Amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptors (GPCR) potently activated by a variety of molecules besides Trace Amines (TAs), including thyroid hormone-derivatives like 3-iodothyronAmine (T1AM), catechol-O-methyltransferase products like 3-methoxytyrAmine, and amphetAmine-related compounds. Accordingly, TAAR1 is considered a promising target for medicinal development. To gain more insights into TAAR1 physiological functions and validation of its therapeutic potential, we recently developed a new class of thyronAmine-like derivatives. Among them compound SG2 showed high affinity and potent agonist activity at mouse TAAR1. In the present work, we describe design, synthesis, and SAR study of a new series of compounds (1–16) obtained by introducing specific structural changes at key points of our lead compound SG2 skeleton. Five of the newly synthesized compounds displayed mTAAR1 agonist activity higher than both SG2 and T1AM. Selected diphenylmethane analogues, namely 1 and 2...
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a homology modelling driven study leading to the discovery of the first mouse Trace Amine associated receptor 5 taar5 antagonists
MedChemComm, 2016Co-Authors: Elena Cichero, Raul R. Gainetdinov, Stefano Espinoza, Andrey S. Gerasimov, Michele Tonelli, Silvia Franchini, Claudia Sorbi, Livio BrasiliAbstract:Several recent studies have focused on a detailed analysis of the Trace Amine-associated receptor type 5 (TAAR5) pharmacology, up to now revealing only a limited number of species-specific ligands, which are also active towards other TAAR receptors. In this context, we developed our work on TAAR5 applying a structure-based computational protocol, revolving around homology modeling and virtual screening calculations. In detail, mTAAR5 and hTAAR5 homology models were built, in order to explore any pattern of structural requirements which could be involved in species-specific differences. Successively, the mTAAR5 model was employed to perform a virtual screening of an in-house library of compounds, including different five-membered ring derivatives, linked to a phenyl ring through a flexible or a rigid basic moiety. The computational protocol applied allowed to select a number of chemical scaffolds that were tested in a biological assay leading to the discovery of the first two mTAAR5 antagonists.
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Trace Amine-Associated Receptor 1 Modulation of DopAmine System
Trace Amines and Neurological Disorders, 2016Co-Authors: Damiana Leo, Stefano EspinozaAbstract:Trace Amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptor belonging to the TAAR family. Discovered in 2001, TAARs have been found in several tissues, ranging from the central nervous system to the olfactory epithelium. The best-studied receptor, TAAR1, is activated by a class of endogenous compounds named Trace Amines (TAs). TAs are structurally related to classic monoAminergic neurotransmitters and found at low concentrations in the mammalian brain. Although TA levels have been associated with many neuropsychiatric disorders, only the discovery of TAAR1 validated their physiological role. TAAR1 can modulate monoAmine neurotransmission and, in particular, the dopAmine system. Several studies have demonstrated that TAAR1 knockout mice display a supersensitive dopAminergic system, while activation of TAAR1 can reduce dopAminergic hyperactivity. For these reasons, TAAR1 has been proposed as a novel therapeutic target for neuropsychiatric disorders such as schizophrenia, bipolar disorder, and addiction.
David K. Grandy - One of the best experts on this subject based on the ideXlab platform.
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ractopAmine a livestock feed additive is a full agonist at Trace Amine associated receptor 1
Journal of Pharmacology and Experimental Therapeutics, 2014Co-Authors: Xuehong Liu, David K. Grandy, Aaron JanowskyAbstract:RactopAmine (RAC) is fed to an estimated 80% of all beef, swine, and turkey raised in the United States. It promotes muscle mass development, limits fat deposition, and reduces feed consumption. However, it has several undesirable behavioral side effects in livestock, especially pigs, including restlessness, agitation, excessive oral-facial movements, and aggressive behavior. Numerous in vitro and in vivo studies suggest RAC’s physiological actions begin with its stimulation of β1- and β2-adrenergic receptor–mediated signaling in skeletal muscle and adipose tissue; however, the molecular pharmacology of RAC’s psychoactive effects is poorly understood. Using human cystic fibrosis transmembrane conductance regulator (hCFTR) chloride channels as a sensor for inTracellular cAMP, we found that RAC and p-tyrAmine (TYR) produced concentration-dependent increases in chloride conductance in oocytes coexpressing hCFTR and mouse Trace Amine–associated receptor 1 (mTAAR1), which was completely reversed by the Trace Amine–associated receptor 1 (TAAR1)–selective antagonist EPPTB [N-(3-ethoxyphenyl)-4-pyrrolidin-1-yl-3-trifluoromethylbenzamide]. Oocytes coexpressing hCFTR and the human β2-adrenergic receptor showed no response to RAC or TYR. These studies demonstrate that, contrary to expectations, RAC is not an agonist of the human β2-adrenergic receptor but rather a full agonist for mTAAR1. Since TAAR1-mediated signaling can influence cardiovascular tone and behavior in several animal models, our finding that RAC is a full mTAAR1 agonist supports the idea that this novel mechanism of action influences the physiology and behavior of pigs and other species. These findings should stimulate future studies to characterize the pharmacological, physiological, and behavioral actions of RAC in humans and other species exposed to this drug.
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exploring the determinants of Trace Amine associated receptor 1 s functional selectivity for the stereoisomers of amphetAmine and methamphetAmine
Journal of Medicinal Chemistry, 2014Co-Authors: Edmund A Reese, James R Bunzow, Katherine L Suchland, Yohei Norimatsu, Madeline Grandy, David K. GrandyAbstract:AmphetAmines are widely abused drugs that interfere with dopAmine transport and storage. Recently, however, another mechanism of action was identified: stereoselective activation of the GαS protein-coupled Trace Amine-associated receptor 1 (TAAR1). To identify structural determinants of this stereoselectivity, we functionally evaluated six mutant receptors in vitro and then used homology modeling and dynamic simulation to predict drug affinities. Converting Asp102 to Ala rendered mouse and rat TAAR1 (mTAAR1 and rTAAR1, respectively) insensitive to β-phenylethylAmine, amphetAmine (AMPH), and methamphetAmine (METH). Mutating Met268 in rTAAR1 to Thr shifted the concentration–response profiles for AMPH and METH isomers rightward an order of magnitude, whereas replacing Thr268 with Met in mTAAR1 resulted in profiles leftward shifted 10–30-fold. Replacing Asn287 with Tyr in rTAAR1 produced a mouselike receptor, while the reciprocal mTAAR1 mutant was rTAAR1-like. These results confirm TAAR1 is an AMPH/METH recep...
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A decade of pharma discovery delivers new tools targeting Trace Amine-associated receptor 1.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2012Co-Authors: Katie R. Tallman, David K. GrandyAbstract:A Decade of Pharma Discovery Delivers New Tools Targeting Trace Amine-Associated Receptor 1
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The Molecular Basis of Species-Specific Ligand Activation of Trace Amine-Associated Receptor 1 (TAAR1)
ACS Chemical Biology, 2009Co-Authors: Edwin S. Tan, David K. Grandy, John C. Naylor, Eli S. Groban, Matthew P. Jacobson, James R Bunzow, Thomas S ScanlanAbstract:The Trace Amine-associated receptor 1 (TAAR1) is an Aminergic G protein-coupled receptor (GPCR) potently activated by 3-iodothyronAmine (1), an endogenous derivative of thyroid hormone. Structure−activity relationship studies on 1 and related agonists showed that the rat and mouse species of TAAR1 accommodated structural modifications and functional groups on the ethylAmine portion and the biaryl ether moiety of the molecule. However, the two receptors clearly exhibited distinct, species-specific ligand preferences despite being remarkably similar with 93% sequence similarity. In this study, we generated single and double mutants of rat and mouse TAAR1 to probe the molecular recognition of agonists and the underlying basis for the ligand selectivity of rat and mouse TAAR1. Key, nonconserved specificity determinant residues in transmembranes helices 4 and 7 within the ligand binding site appear to be the primary source of a number of the observed ligand preferences. Residue 7.39 in transmembrane 7 dictated...
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cardiac effects of Trace Amines pharmacological characterization of Trace Amine associated receptors
European Journal of Pharmacology, 2008Co-Authors: Sabina Frascarelli, Grazia Chiellini, David K. Grandy, Thomas S Scanlan, Sandra Ghelardoni, Romina Vargiu, Simonetta Roncatestoni, Riccardo ZucchiAbstract:Trace Amine-associated receptors, a novel class of G-protein coupled receptors which respond to Trace Amines but not to classical biogenic Amines, have been found to be expressed in heart. Therefore, we investigated the cardiac effects of the Trace Amines p-tyrAmine, beta-phenylethylAmine, octopAmine, and tryptAmine. Isolated rat hearts were perfused in the presence of Trace Amines, monitoring the hemodynamic variables. In addition, radioligand binding experiments with [3H]-p-tyrAmine and [125I]-3-iodothyronAmine were performed in rat ventricular tissue. OctopAmine, beta-phenylethylAmine, and tryptAmine produced a dose-dependent negative inotropic effect as shown by reduced cardiac output (IC(50)=109 microM, 159 microM, and 242 microM, respectively). In the same preparation a similar effect was produced by thyronAmine and 3-iodothyronAmine, with IC(50)=94 microM and 27 microM, respectively. The negative inotropic effect of octopAmine was confirmed in a papillary muscle preparation. All Trace Amines except tryptAmine increased the heart rate, but this action could be attributed to their sympathomimetic properties, since it was abolished by propranolol. The negative inotropic effect of Trace Amines was significantly increased by the tyrosine kinase inhibitor genistein. Specific and saturable binding of [(3)H]-p-tyrAmine and [125I]-3-iodothyronAmine was observed in ventricular tissue. While [3H]-p-tyrAmine was displaced by 3-iodothyronAmine, [(125)I]-3-iodothyronAmine was not displaced by p-tyrAmine. In conclusion, Trace Amines and thyronAmines are negative inotropic agents. Their effect appears to be mediated by a subtype of Trace Amine-associated receptor which is characterized by the rank of potency: 3-iodothyronAmine > thyronAmine = octopAmine = beta-phenylethylAmine, while tryptAmine and p-tyrAmine are significantly less active.
Marius C. Hoener - One of the best experts on this subject based on the ideXlab platform.
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activation of Trace Amine associated receptor 1 attenuates schedule induced polydipsia in rats
Neuropharmacology, 2019Co-Authors: I. Sukhanov, Marius C. Hoener, Raul R. Gainetdinov, Antonina Dolgorukova, Artem Dorotenko, Anton BespalovAbstract:Trace Amine Associated Receptor 1 (TAAR1) is a novel pharmacological target. TAAR1 are well-documented to play a modulatory role in the dopAminergic system. In spite of a growing number of studies of TAAR1 effects, little is still known about the behavioral pharmacology of TAAR1 ligands, including effects of repeated TAAR1 agonist administration. The present study appears to be the first that estimated the action of TAAR1 agonists on schedule-induced polydipsia, a type of adjunctive behavior, which is considered to be useful for evaluating certain aspects of obsessive-compulsive and related disorders (OCD) and schizophrenia. Our results have demonstrated that the wide range of RO5263397, the highly selective partial TAAR1 agonist, doses (1-10 mg/kg) attenuated the polydipsia induced by two different schedules of food delivery in rats. The effect remained unchanged for the 7 days of repeated treatment. However, the highest tested doses of RO5263397 (6 and 10 mg/kg) decreased the vertical locomotor activity of the animals and the volume of water intake of thirsty rats following the acute treatment. Also, though, the repeated RO5263397 administration is exhibited to diminish the volume of consumed water and weight of rats without SIP, on the other hand, the tolerance was observed to these drug effects. In general, the RO5263397 decreases specifically the adjunctive drinking and this effect is maintained with repeated drug administration without the development of tolerance. The interpretation of these results as an evidence for the RO5263397 anticompulsive-like action, however, should be taken with caution because the drug also influenced the drinking behavior and only weakly affected the other parameters of SIP used to reveal the potential anticompulsive-like effects of drugs.
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pharmacology of human Trace Amine associated receptors therapeutic opportunities and challenges
Pharmacology & Therapeutics, 2017Co-Authors: Mark D. Berry, Marius C. Hoener, Raul R. Gainetdinov, Mohammed ShahidAbstract:Abstract The discovery in 2001 of a G protein-coupled receptor family, subsequently termed Trace Amine-associated receptors (TAAR), triggered a resurgence of interest in so-called Trace Amines. Initial optimism quickly faded, however, as the TAAR family presented a series of challenges preventing the use of standard medicinal chemistry and pharmacology technologies. Consequently the development of basic tools for probing TAAR and translating findings from model systems to humans has been problematic. Despite these challenges the last 5 years have seen considerable advances, in particular with respect to TAAR1, which appears to function as an endogenous rheostat, maintaining central neurotransmission within defined physiological limits, in part through receptor heterodimerization yielding biased signaling outputs. Regulation of the dopAminergic system is particularly well understood and clinical testing of TAAR1 directed ligands for schizophrenia and psychiatric disorders have begun. In addition, pre-clinical animal models have identified TAAR1 as a novel target for drug addiction and metabolic disorders. Growing evidence also suggests a role for TAARs in regulating immune function. This review critically discusses the current state of TAAR research, highlighting recent developments and focussing on human TAARs, their functions, and clinical implications. Current gaps in knowledge are identified, along with the research reagents and translational tools still required for continued advancement of the field. Through this, a picture emerges of an exciting field on the cusp of significant developments, with the potential to identify new therapeutic leads for some of the major unmet medical needs in the areas of neuropsychiatry and metabolic disorders.
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Trace Amine associated receptor 1 agonists as narcolepsy therapeutics
Biological Psychiatry, 2017Co-Authors: Sarah Black, Marius C. Hoener, Michael D. Schwartz, Tsuiming Chen, Thomas S KilduffAbstract: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.
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a partial Trace Amine associated receptor 1 agonist exhibits properties consistent with a methamphetAmine substitution treatment
Addiction Biology, 2017Co-Authors: Yue Pei, Marius C. Hoener, Aman Asifmalik, Juan J. CanalesAbstract:Recent evidence suggests that the Trace Amine-associated receptor 1 (TAAR1) plays a pivotal role in the regulation of dopAmine (DA) transmission and psychostimulant action. Several selective TAAR1 agonists have previously shown efficacy in models of cocaine addiction. However, the effects of TAAR1 activation on methamphetAmine (METH)-induced behaviours are less well understood, as indeed are the underlying neurochemical mechanisms mediating potential interactions between TAAR1 and METH. Here, in a progressive ratio schedule of reinforcement the partial TAAR1 agonist, RO5263397, reduced the break-point for METH self-administration, while significantly increasing responding maintained by food reward. Following self-administration and extinction training, RO5263397 completely blocked METH-primed reinstatement of METH seeking. Moreover, when used as a substitute, unlike a low dose of METH, which sustained vigorous responding when substituting for the training dose of METH, RO5263397 was not self-administered at any dose, thus exhibiting no apparent abuse liability. Fast-scan cyclic voltammetry experiments showed that RO5263397 prevented METH-induced DA overflow in slices of the nucleus accumbens, while having no effect on DA transmission in its own right. Collectively, the present observations demonstrate that partial TAAR1 activation decreases the motivation to self-administer METH, blocks METH-primed reinstatement of METH seeking and prevents METH-induced DA elevations in the nucleus accumbens, and strongly support the candidacy of TAAR1-based medications as potential substitute treatment in METH addiction.
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in vitro characterization of psychoactive substances at rat mouse and human Trace Amine associated receptor 1
Journal of Pharmacology and Experimental Therapeutics, 2016Co-Authors: Linda D Simmler, Marius C. Hoener, Daniele Buchy, Sylvie Chaboz, Matthias E LiechtiAbstract:Trace Amine-associated receptor 1 (TAAR1) has been implicated in the behavioral effects of amphetAmine-type stimulant drugs in rodents. TAAR1 has also been suggested as a target for novel medications to treat psychostimulant addiction. We previously reported that binding affinities at TAAR1 can differ between structural analogs of psychostimulants, and species differences have been observed. In this study, we complement our previous findings with additional substances and the determination of functional activation potencies. In summary, we present here pharmacological in vitro profiles of 101 psychoactive substances at human, rat, and mouse TAAR1. p-TyrAmine, β-phenylethylAmine, and tryptAmine were included as endogenous comparator compounds. Functional cAMP measurements and radioligand displacement assays were conducted with human embryonic kidney 293 cells that expressed human, rat, or mouse TAAR1. Most amphetAmines, phenethylAmine, and aminoindanes exhibited potentially physiologically relevant rat and mouse TAAR1 activation (EC50 10 µM) binding properties at TAAR1. Pipradrols, including methylphenidate, exhibited no affinity for TAAR1. We found considerable species differences in activity at TAAR1 among the highly active ligands, with a rank order of rat > mouse > human. This characterization provides information about the pharmacological profile of psychoactive substances. The species differences emphasize the relevance of clinical studies to translationally complement rodent studies on the role of TAAR1 activity for psychoactive substances.