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Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics


Revel, FG and Moreau, JL and Gainetdinov, RR and Ferragud, A and Velazquez-Sanchez, C and Sotnikova, TD and Morairty, SR and Harmeier, A and Groebke Zbinden, K and Norcross, RD and Bradaia, A and Kilduff, TS and Biemans, B and Pouzet, B and Caron, MG and Canales, JJ and Wallace, TL and Wettstein, JG and Hoener, MC, Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics, Biological psychiatry, 72, (11) pp. 934-942. ISSN 0006-3223 (2012) [Refereed Article]

DOI: doi:10.1016/j.biopsych.2012.05.014


Background: Trace amines, compounds structurally related to classical biogenic amines, represent endogenous ligands of the trace amine-associated receptor 1 (TAAR1). Because trace amines also influence the activity of other targets, selective ligands are needed for the elucidation of TAAR1 function. Here we report on the identification and characterization of the first selective and potent TAAR1 partial agonist.

Methods: The TAAR1 partial agonist RO5203648 was evaluated for its binding affinity and functional activity at rodent and primate TAAR1 receptors stably expressed in HEK293 cells, for its physicochemical and pharmacokinetic properties, for its effects on the firing frequency of monoaminergic neurons ex vivo, and for its properties in vivo with genetic and pharmacological models of central nervous system disorders.

Results: RO5203648 showed high affinity and potency at TAAR1, high selectivity versus other targets, and favorable pharmacokinetic properties. In mouse brain slices, RO5203648 increased the firing frequency of dopaminergic and serotonergic neurons in the ventral tegmental area and the dorsal raphe nucleus, respectively. In various behavioral paradigms in rodents and monkeys, RO5203648 demonstrated clear antipsychotic- and antidepressant-like activities as well as potential anxiolytic-like properties. Furthermore, it attenuated drug-taking behavior and was highly effective in promoting attention, cognitive performance, and wakefulness.

Conclusions: With the first potent and selective TAAR1 partial agonist, RO5203648, we show that TAAR1 is implicated in a broad range of relevant physiological, behavioral, and cognitive neuropsychiatric dimensions. Collectively, these data uncover important neuromodulatory roles for TAAR1 and suggest that agonists at this receptor might have therapeutic potential in one or more neuropsychiatric domains.

Item Details

Item Type:Refereed Article
Research Division:Psychology
Research Group:Biological psychology
Research Field:Behavioural neuroscience
Objective Division:Expanding Knowledge
Objective Group:Expanding knowledge
Objective Field:Expanding knowledge in psychology
UTAS Author:Canales, JJ (Professor Juan Canales)
ID Code:121299
Year Published:2012
Web of Science® Times Cited:111
Deposited By:Psychology
Deposited On:2017-09-21
Last Modified:2017-09-21

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