TAAR1 dependent and independent actions of the potential antipsychotic and dual TAAR1/5-HT1A receptor agonist SEP-363856

Abstract SEP-363856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D 2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxyt...

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Published in:Neuropsychopharmacology (New York, N.Y.) N.Y.), 2022-12, Vol.47 (13), p.2319-2329
Main Authors: Saarinen, Marcus, Mantas, Ioannis, Flais, Ivana, Ågren, Richard, Sahlholm, Kristoffer, Millan, Mark J., Svenningsson, Per
Format: Article
Language:English
Subjects:
Agonists
Antipsychotics
Body temperature
Confocal microscopy
Dizocilpine
Dopamine D2 receptors
Electrophysiology
Locomotion
Mental disorders
Potassium channels (inwardly-rectifying)
Psychosis
Psychotropic drugs
Schizophrenia
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Summary:Abstract SEP-363856 (SEP-856) is a novel antipsychotic under clinical development. It displays a unique pattern of receptor interaction, with only weak (partial agonist) activity at dopamine D 2 receptors, yet more potent agonist activity at the trace amine associated receptor (TAAR1) and 5-hydroxytryptamine 1 A receptor (5-HT 1A ). Nonetheless, these observations await independent confirmation and more detailed characterization of the in vitro and in vivo actions of SEP-856 at TAAR1 and 5-HT 1A receptors would be instructive. Herein, we employed luminescence complementation technology in heterologous live cell systems, confocal microscopy, voltage clamp electrophysiology, behavioral readouts and TAAR1 knockout (KO) mice to study SEP-856 in further detail. We provide evidence for the ability of SEP-856 to activate TAAR1 at the surface plasma membrane, and show that this interaction results in Gα s recruitment (pEC 50 : 6.08 ± 0.22 E MAX : 96.41% ± 15.26) and by extension, to G-protein inwardly rectifying potassium (GIRK) channel activation. Using TAAR1-KO mice, we find TAAR1 to be indispensable for SEP-856 control of body temperature, baseline locomotion reduction and for “antipsychotic-like” efficacy as characterized by a reversal of dizocilipine (MK-801) mediated disruption of pre-pulse inhibition. Conversely, the inhibition by SEP-856 of MK-801 induced locomotion was unaffected in TAAR1 KO mice. SEP-856 behaved as a low-potency, partial agonist at the 5-HT 1A receptor, while it partially inhibited recruitment of D 2 receptor-coupled Gα and GIRK by DA and acted as a weak partial agonist with low potency at the same receptor when applied alone. Our findings corroborate and extend previous observations on the molecular substrates engaged by this unique, dual TAAR1/5-HT 1A receptor agonist and potential antipsychotic that could prove to have major advantages in the treatment of schizophrenia and other psychotic disorders.
ISSN:0893-133X
1740-634X
DOI:10.1038/s41386-022-01421-2