Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety

Neuropharmacology. 2013 Jul;70:338-47. doi: 10.1016/j.neuropharm.2013.02.024. Epub 2013 Mar 13.

Abstract

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.

MeSH terms

  • Adrenergic Uptake Inhibitors
  • Animals
  • Anti-Anxiety Agents / pharmacology
  • Antidepressive Agents / pharmacology
  • Antidepressive Agents / therapeutic use
  • Anxiety / drug therapy*
  • Behavior, Animal / drug effects*
  • Cerebral Cortex / drug effects
  • Cerebral Cortex / metabolism
  • Cyclohexanols / pharmacology
  • Cyclopropanes / pharmacology*
  • Cyclopropanes / therapeutic use
  • Depression / drug therapy*
  • Dopamine / metabolism
  • Duloxetine Hydrochloride
  • Humans
  • Male
  • Mice
  • Milnacipran
  • Motor Activity / drug effects
  • Neurotransmitter Transport Proteins / antagonists & inhibitors*
  • Norepinephrine / metabolism
  • Rats
  • Serotonin / metabolism
  • Synaptosomes / drug effects
  • Thiophenes / pharmacology
  • Venlafaxine Hydrochloride

Substances

  • Adrenergic Uptake Inhibitors
  • Anti-Anxiety Agents
  • Antidepressive Agents
  • Cyclohexanols
  • Cyclopropanes
  • Neurotransmitter Transport Proteins
  • Thiophenes
  • Serotonin
  • Venlafaxine Hydrochloride
  • Duloxetine Hydrochloride
  • Milnacipran
  • Dopamine
  • Norepinephrine