Comparative Study Of Antidepressive Effects Of The Four Isomers Of SIPIyy24

Objective: To study and compare the effects of the monoamine reuptake inhibition of four isomers of SIPIyy24 in vitro, and to verify the antidepressive effects and toxicity of the four compounds in vivo. On these bases, we shall choose a single isomer as a new antidepressant drug to explore.Methods: To study the effect of monoamine reuptake inhibition of four isomers of SIPIyy24 (erythro form racemic: SIPIyy24-A1, SIPIyy24-A2, threo form racemic: SIPIyy24-B1, SIPIyy24-B2) by using the isotopes-marker assay in vitro. In vivo study, we used the Forced Swimming Test (FST) and the Tail Suspension Test (TST), which belong to the behavioural despair test, to investigate the antidepressive effects of the four coumpounds. Safety of four isomers of SIPIyy24 were evaluated by measuring LD50.Results: 1. In vitro study, SIPIyy24-A1 was the most effective in inhibiting the reuptake of 5-HT by brain synaptosomes among the four isomers of SIPIyy24, and its IC₅₀(0.012μM) was lower than the Venlafaxine's IC (0.35μM). Similarly, SIPIyy24-A1 was the most effective in inhibiting the reuptake of NA by 50brain synaptosomes among the four isomers of SIPIyy24, and its IC₅₀(0.185μM) was also lower than Venlafaxine's IC₅₀(1.4μM). SIPIyy24-A1 (IC₅₀: 1.15μM) was more effective than SIPIyy24-A2 (IC₅₀: 10.0μM) in inhibiting the reuptake of ³H-DA by brain synaptosomes. SIPIyy24-B1 and SIPIyy24-B2 had no inhibitory effects in reuptake of ³H-DA. 2. In vivo study, the four isomers of SIPIyy24 had considerable antidepressive effects. They decreased significantly the immobile time of mice in FST and TST (P < 0.05 or P < 0.01, vs control). SIPIyy24-A1 had best drug action among the four isomers. Its single dose is 15-30mg/kg, and it is 10-20mg/kg after one-week per os. In toxicity tests, the LD₅₀ of SIPIyy24-A1 (1030-1202 mg/kg) and SIPIyy24-A2 (1171-1259mg/kg) were larger than those of SIPIyy24-B1 (300-400mg/kg) and SIPIyy24-B2 (200-250mg/kg).Conclusion: In vitro study, the four isomers of SIPIyy24 inhibited effectively the reuptake of 5-HT and NA by brain synaptosomes. SIPIyy24-A1 and SIPIyy24-A2 also showed inhibitory effects for DA. In vivo study, all of the four isomers of SIPIyy24 showed excellent anti-depressive effects, and among of them SIPIyy24-A1 had best drug action. The safe range of erythro form racemic was 5-6 times larger than that of threo form racemic. So SIPIyy24-A1 possessed the best drug's activity and lower toxicity among the four isomers of SIPIyy24. SIPIyy24-A1 was the most valuable and feasible among the four isomers of SIPIyy24 as a new drug to explore.