Trace amine-associated receptor 1 partial agonism reveals novel paradigm for neuropsychiatric therapeutics.
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.
Neuroscience Research, Pharmaceuticals Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
Florent G
FG
Revel
Jean-Luc
JL
Moreau
Raul R
RR
Gainetdinov
Antonio
A
Ferragud
Clara
C
Velázquez-Sánchez
Tatyana D
TD
Sotnikova
Stephen R
SR
Morairty
Anja
A
Harmeier
Katrin
K
Groebke Zbinden
Roger D
RD
Norcross
Amyaouch
A
Bradaia
Thomas S
TS
Kilduff
Barbara
B
Biemans
Bruno
B
Pouzet
Marc G
MG
Caron
Juan J
JJ
Canales
Tanya L
TL
Wallace
Joseph G
JG
Wettstein
Marius C
MC
Hoener
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D010080:Oxazoles / Q000494:pharmacology*; D011903:Raphe Nuclei / Q000187:drug effects* / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D059326:Serotonergic Neurons / Q000187:drug effects* / Q000502:physiology; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000502:physiology; D000095383:Trace Amine-Associated Receptors
D010080:Oxazoles; D043562:Receptors, G-Protein-Coupled; D000095383:Trace Amine-Associated Receptors; C580579:4-(3,4-dichlorophenyl)-4,5-dihydrooxazol-2-ylamine