Levomilnacipran (LVM; F2695) is the more active enantiomer of the
serotonin/
norepinephrine (5-HT/NE) reuptake inhibitor (
SNRI)
milnacipran and is currently under development for the treatment of
major depressive disorder. LVM was benchmarked against two other
SNRIs,
duloxetine and
venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and
5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and
5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for
norepinephrine relative to
serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with
venlafaxine and
duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of
5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced
shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg).
Duloxetine and
venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and
5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects.