Toloxatone

Toloxatone (MD 69276) is a reversible, selective MAO-A inhibitor that can cross the blood-brain barrier. Toloxatone increases the levels of serotonin (5-HT) and norepinephrine in the brain. Toloxatone reduces the immobility time in the forced swimming test in mice, inhibits killing behavior in rats without causing sedation, and shows a correlation between its free plasma concentration and cerebrospinal fluid concentration. Toloxatone is widely used in research related to depression, depressive disorders and Parkinson's disease^[1][2][3][4]. In Vitro:Toloxatone (3-100 μM; 180 minutes) concentration-dependently decreases medium levels of DOPAL, DOPAC, DOPET, and DOPA and increases medium dopamine levels in rat pheochromocytoma PC12 cells, but requires relatively high concentrations to exert these effects^[1]. In Vivo:Toloxatone (5-10 mg/kg; i.v.; single injection) exhibits dose-proportional pharmacokinetics over 5-10 mg/kg i.v. in anaesthetized male Fauve de Bourgogne rabbits, with a short terminal half-life (41.5-47.4 minutes for total drug), moderate volume of distribution (5.4-5.8 L), high total clearance (79-106 mL/min), weak plasma protein binding (28.1-32.2%), and rapid blood-brain barrier penetration resulting in CSF concentrations equivalent to unbound plasma concentrations^[2].
Toloxatone (24.2-72.5 μmol/kg; i.p.; single dose) produces dose-dependent, sedation-independent inhibition of mouse killing behavior in spontaneous killer Wistar rats, with a maximum 82% inhibition observed at 72.5 μmol/kg (i.p.)^[3].
Toloxatone (48.3 μmol/kg; i.p.; single dose) inhibits mouse killing behavior in PCPA (HY-B1368)-induced killer Wistar rats with 50% maximum inhibition at 48.3 μmol/kg (i.p.), with efficacy comparable to that seen in spontaneous killer rats^[3].
Toloxatone (48.3 μmol/kg; i.p.; single dose) inhibits mouse killing behavior (MKB) in raphectomized killer Wistar rats with 58% maximum inhibition at 48.3 μmol/kg (i.p.), with efficacy comparable to that seen in spontaneous killer rats^[3].
Toloxatone (256 mg/kg; i.p.; single acute dose; 30 minutes prior to test) produces a significant anti-immobility effect in the mouse forced swimming test model of depression, which is completely reversed by co-administration of diazepam 2 mg/kg^[4].