Trace Amine-Associated Receptor 1 Partial Agonism Reveals Novel Paradigm for Neuropsychiatric Therapeutics

Revel, Florent G.; Moreau, Jean‐Luc; Gainetdinov, Raul R.; Ferragud, Antonio; Velázquez-Sánchez, Clara; Sotnikova, Tatyana D.; Morairty, Stephen R.; Harmeier, Anja; Zbinden, Katrin Groebke; Norcross, Roger D.; Bradaı̈a, Amyaouch; Kilduff, Thomas S.; Biemans, Barbara; Pouzet, Bruno; Caron, Marc G.; Canales, Juan J.; Wallace, Tanya L.; Wettstein, Joseph G.; Hoener, Marius C.

doi:10.1016/j.biopsych.2012.05.014

Cited by 158 publications

(157 citation statements)

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“…This is in agreement with the finding that both the endogenous agonist p-tyramine and the selective TAAR1 agonist RO5166017 suppressed the firing frequency of DA neurons [23,24], whereas the selective antagonist EPPTB increased it [25]. However, the partial agonist, RO5203648, increased the firing rate of DA neurons [26], suggesting that TAAR1 can control DA transmission in opposite ways depending on ambient levels of trace amines. This unique feature of TAAR1 may be highly relevant for the treatment of stimulant addiction.…”

Section: Paving An Indirect Path To Treat Addictionsupporting

confidence: 90%

“…Recently, we have provided the first evidence that TAAR1 regulates stimulant self-administration. The TAAR1 partial agonist, RO5203648, dosedependently reduced cocaine intake in a self-administration paradigm [26]. Our preliminary observations also indicate that TAAR1 activation prevents relapse to cocaine seeking (unpublished observations).…”

Section: Paving An Indirect Path To Treat Addictionsupporting

confidence: 65%

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The Trace of Non-classical Biogenic Amines: A New Road to Addiction Recovery

Canales¹

2013

J Addict Res Ther

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Stimulant abuse is prevalent according to recent global epidemiological studies. Research into treatment for problematic stimulant abuse has yet to find a suitable pharmacotherapeutic agent to assist with detoxification, withdrawal and relapse prevention. The newly discovered trace amine-associated receptor 1 (TAAR1) constitutes a novel receptor target for medication development with significant potential to treat the pathological changes produced by chronic drug exposure, especially stimulant abuse. Here, I briefly review evidence indicating that TAAR1 modulates the activity of the dopamine system and strongly influences the neurochemical and behavioral actions of psychomotor stimulants. The evidence discussed confirms the view that TAAR1 is a promising candidate receptor for the design of new effective addiction therapies. The Classical Direct ApproachThe classical biogenic amines have been under the spotlight in the fields of neuropharmacology and neuropsychiatry for the past 50 years. Historically, the search for treatments for psychopathological disorders such as depression, anxiety and schizophrenia has focused on the receptors, transporters and metabolic pathways for three catecholamines -dopamine (DA), norepinephrine and epinephrine-, histamine and serotonin, and to a lesser extent on amino acid transmitters and their receptors. Biogenic amines play a fundamental role in modulating a wide variety of physiological and behavioural processes, including autonomic function, hormone regulation and motor control, and are believed to contribute critically to emotional and cognitive function, neurotoxicity and mental disease [1][2][3]. The advent of drugs aimed at these classical targets to treat affective and psychotic disorders remains to this date the single most relevant advance in pharmacotherapy but the discovery of these drugs was serendipitous. It did not derive from the identification of the neuronal and circuitlevel alterations underlying psychiatric illness. This lack of mechanistic understanding hampered the progress and further development of therapeutic agents. An area in which development of pharmacological treatments has been particularly difficult is addiction and addictiverelated disorders, most notably addiction to cocaine and amphetaminetype substances. Stimulant addiction is widely recognized for its treatment challenges [4,5]. Although several forms of non-specific pharmacology are currently in use, including anti-depressants and antiepileptic drugs, there are no specific and proven medications that can be used to facilitate detoxification, enhance retention in psychotherapy and generally promote quicker recovery from chronic stimulant abuse.Changes in DA transmission are critical for understanding the acute and long-term effects of chronic stimulant exposure. The ability of cocaine-like drugs to maintain self-administration in rodents is correlated with their potency in inhibiting the dopamine transporter (DAT) [6]. Moreover, the self-reported "high" induced by stimulants in humans appears ...

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Section: Paving An Indirect Path To Treat Addictionsupporting

confidence: 90%

Section: Paving An Indirect Path To Treat Addictionsupporting

confidence: 65%

The Trace of Non-classical Biogenic Amines: A New Road to Addiction Recovery

Canales¹

2013

J Addict Res Ther

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“…To our knowledge, 36 was the first selective partial TAAR1 agonist tested in behavioral studies, and it clearly demonstrated antipsychotic, antidepressant, and antiaddictive activities in a number of animal models. 20,21 Unfortunately, additional in vitro testing of 36 revealed a very high metabolic clearance of this compound in human hepatocytes, which was not obvious in prior testing in human liver microsomes, and this led to a deselection of 36 for further development. These observations prompted us to compare in vitro microsomal clearance with in vitro hepatocyte clearance for a number of other compounds from the same series, whereby a surprisingly big discrepancy between the clearance data in the two assay systems was apparent for most of the compounds (Table 5).…”

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confidence: 99%

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Galley

Beurier

Décoret

et al. 2016

ACS Med. Chem. Lett.

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2-Aminooxazolines were discovered as a novel structural class of TAAR1 ligands. Starting from a known adrenergic compound 1, structural modifications were made to obtain highly potent and selective TAAR1 ligands such as 12 (RO5166017), 18 (RO5256390), 36 (RO5203648), and 48 (RO5263397). These compounds exhibit drug-like physicochemical properties, have good oral bioavailability, and display in vivo activity in a variety of animal models relevant for psychiatric diseases and addiction. KEYWORDS: TAAR1 agonist, 2-aminooxazoline, SAR, schizophrenia T race amines (TAs) are metabolites of amino acids with structural similarity to biogenic amines and represent the endogenous ligands of the trace amine associated receptor 1 (TAAR1). 1,2 Dysregulation of TAs in the brain has been linked to a variety of psychiatric diseases and selective TAAR1 ligands have gained much interest as potential therapeutics for depression, schizophrenia, bipolar disorder, ADHD, and psychostimulant addiction. 3 The modulatory role of this G protein-coupled receptor on monoaminergic neurotransmission has recently been investigated and confirmed by characterization of a transgenic mouse line overexpressing TAAR1 in central nervous system neurons. 4 Further efforts were made to identify potent and selective TAAR1 agonists with favorable pharmacokinetic properties in order to prove the modulatory effect on dopaminergic signaling in vivo. 5 In an endeavor to discover a novel and selective TAAR1 chemotype, we considered application of the SOSA approach (Selective Optimization of Side Activities) to adrenergic ligands as a viable lead identification strategy. 6 Structural similarity of TAAR1 agonists with adrenergic agonists was already known from our previous work 5 pointing toward a similarity of the binding regions of both receptors. 7,8 Therefore, we searched the literature and in-house databases for adrenergic ligands reported as drugs or development candidates, whereupon the alpha 2 adrenergic receptor partial agonist S18616 from Servier (1) caught our attention. 9 Pleasingly, testing this candidate revealed (besides its expected activity at the human α 2A receptor) a high functional activity at human TAAR1 (EC 50 = 15 nM). 10 A medicinal chemistry optimization program was then started aiming for compounds selective for TAAR1, where the known TAAR1 pharmacophore motif (aromatic moiety linked to a basic headgroup) of S18616 was kept, but the linker region was modified by opening the central six-membered ring (Figure 1). For all such derived compounds selectivity data was obtained by measuring functional activity at the human TAAR1 receptor (EC 50 hTAAR1) and in addition at the human adrenergic α 2A receptor (hα 2A ) (Table 1).All 2-aminooxazolines were synthesized from the corresponding amino alcohols 15 and cyanogen bromide in the presence of a base as depicted in Scheme 1. The enantiomerically pure amino alcohols were obtained from the chiral pool (e.g., via reduction of amino acids or their derivatives). The procedures are describ...

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“…Rats were instrumented with sterile telemetry transmitters (F40-EET, Data Sciences Inc., St Paul, MN) as previously described Revel et al, 2012Revel et al, , 2013. Briefly, under isoflurane anesthesia, transmitters were placed intraperitoneally and biopotential leads were routed subcutaneously to the head and neck.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

Kilduff¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE (DD-MM-YYYY)September 2014 (From -To) REPORT TYPE Annual DATES COVERED P ERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER SRI InternationalMenlo Park, CA 94025-3493 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENT SUPPLEMENTARY NOTES ABSTRACTDuring Year 5, we continued tests of the hypothesis that disfacilitation of wake-promoting systems by the hypocretin (Hcrt) receptor antagonist almorexant (ALM) results in less functional impairment than the inhibition of neural activity produced by the benzodiazepine receptor agonist zolpidem (ZOL). One paper was published (Morairty et al. 2014), another has been accepted for publication (Dittrich et al., in press) and a third is in resubmission (Vazquez-DeRose et al., submitted). Data collection for Aims 2c and 3b.2 have been completed and data analysis ongoing; manuscripts will be written and submitted during Year 6. Data collection and analysis of Aim 3a is nearing completion; an abstract summarizing this work has been submitted for presentation at the 2014 Society for Neuroscience meeting. Data collection for Aims 3b.3, 4c and 6a have been initiated. The overall results obtained to date are consistent with the hypothesis that the hypocretin/orexin antagonist ALM produces less functional impairment than the benzodiazepine receptor agonist zolpidem (ZOL) because ZOL causes a general inhibition of neural activity whereas ALM specifically disfacilitates wake-promoting systems. SUBJECT TERMSSleep, performance, drug, neurotransmitter, hypocretin, orexin, benzodiazepine, zolpidem, neurochemistry, microdialysis INTRODUCTIONAlmorexant (ALM) is a hypocretin/orexin (Hcrt) receptor antagonist with a novel mechanism of action that has shown promise as an effective hypnotic. Preclinical data demonstrate that animals treated with ALM are easily aroused from sleep and are free of ataxia and other behavioral impairments. If this observation is confirmed in humans, it would have enormous implications for the management of disturbed sleep in both military a...

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Trace Amine-Associated Receptor 1 Partial Agonism Reveals Novel Paradigm for Neuropsychiatric Therapeutics

Cited by 158 publications

References 59 publications

The Trace of Non-classical Biogenic Amines: A New Road to Addiction Recovery

The Trace of Non-classical Biogenic Amines: A New Road to Addiction Recovery

Discovery and Characterization of 2-Aminooxazolines as Highly Potent, Selective, and Orally Active TAAR1 Agonists

Effect of a Hypocretin/Orexin Antagonist on Neurocogniive Performance

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