RESUMEN
Currently, most commercially available antidepres-sants have one or more chiral centers,and development of chiral antidepressants are of great interest for researchers. Thalidomide induced tragedy promotes drug evaluation centers from various countries to reevaluate their current guidelines and recommend single enantiomer application when developing a chiral antide-pressant. Unfortunately,as far to our knowledge,traditional en-antiomers comparison and active enantiomer selection are real-ized by simple comparison using in vitro targets data. Our team established an integrated system for chiral antidepressant evalua-tion and active enantiomer screening based on four modules,in-cluding pharmacodynamic comparison,pharmacokinetic compar-ison, toxicological comparison, and comprehensive factors. Here,we review this integrated system and make a detailed a-nalysis taking ammoxetine as a realistic example.
RESUMEN
OBJECTIVE To study the antidepressant effects of ammoxetine(AMX)and the underlying mechanisms. METHODS Two behavioral despair models,the tail suspension test (TST) and the forced swimming test(FST),were used to evaluate the antidepressant-like effects of AMX 2.5-20 mg · kg-1 following oral administration. Monoamine neurotransmitter p-chloro-phenylalanine(p-CPA)andα-methyl-p-tyrosine(AMPT) depletion models in mice were used to investigate the effects of AMX on levels of 5-serotomin(5-HT)and norepinephrine(NE)in the brain. RESULLTS The results of behavioral study showed that compared with normal control group,AMX(10 and 20 mg · kg-1)reduced the immobility time of mice by 51.4% and 80.7% in the TST(P<0.05,P<0.01) or by 48.0% and 66.2% in the FST (P<0.05),respectively. Locomotion activity test indicated that AMX did not increase or decrease the movement distance of mice,demonstrating that AMX had no excitatory or inhibitory actions on the central nervous system. Moreover,AMX(5,10 and 20 mg·kg-1)exerted antidepressant effects in the p-CPA induced 5-HT depletion model and AMPT induced NE depletion model,as evidenced by the significantly reduced immobility time,ie,63.9%,93.4%,90.5% and 61.9%,77.2%,100% reduction in the TST (P<0.01),respectively,and AMX at the dose of 20 mg·kg-1 significantly increased the concentrations of 5-HT and NE by 144.7% and 57.2% in the mouse brain(P<0.05) ,respectively. CONCLUSION AMX has strong antidepressant-like effects in behavioral despair models and monoamine neurotransmitter depletion models in mice,which is involved in the increased levels of 5-HT and NE in the brain.