Dasotraline hydrochloride (SEP-225289 hydrochloride) is a triple reuptake inhibitor that inhibits dopamine, norepinephrine, and serotonin transporters with IC50 values of 4, 6, and 11 nM, respectively.

Dopamine:4nM, Norepinephrine:6nM, SERT:11 nM

Acute administration of dasotraline decreases the spontaneous firing rate of LC NE (norepinephrine), VTA DA (dopamine), and DR 5-HT (serotonin) neurons in a dose-dependent manner by activating α2, D2, and 5-HT1A autoreceptors, respectively. Primarily, dasotraline significantly reduces the firing rate of LC NE neurons, while moderately impacting VTA DA and DR 5-HT neuronal activity. Concurrently, SEP-225289, known as (dasotraline), demonstrates equal potency in inhibiting both 5-HT and NE transporters, effectively extending the time for a 50% recuperation of firing activity in dorsal hippocampus CA3 pyramidal neurons following the inhibition induced by the microiontophoretic application of 5-HT and NE. Moreover, the average occupancies of dopamine and serotonin transporters by SEP-225289 escalate with dose increments, showing transporter occupancies of approximately 33%±11% and 2%±13% for 8 mg, 44%±4% and 9%±10% for 12 mg, and 49%±7% and 14%±15% for 16 mg, for dopamine and serotonin transporters, respectively.