Design, Synthesis And Biological Evaluation Of Novel Series Of Antidepressants

Since the first generation of tricyclic antidepressants was discovered in the 1950s, three generation antidepressants have been developed up to now. But one of the main drawbacks of the currently available antidepressants is their slow onset of action, namely, all antidepressants need to be administered for 2-6 weeks to produce a significant clinical improvement. Although the second-generation antidepressants of SSRIs have improved this lag, 2-4 weeks are still needed. Even the third-generation antidepressants with new mechanisms such as duloxetine and venlaxine still required 2 weeks of action. So antidepressants with rapid onset of action are critically required.In this paper, the literatures before June, 2006 about new achievements of antidepressants were reviewed. Currently, investigation on antidepressants is focused on strategies for producing faster acting antidepressants with new mechanisms based on the SSRI'plus'method. Although some compounds exhibited selective and high affinity at the 5-HT1A receptor and serotonin reuptake inhibition for dual activities, some compounds were only a new classes of 5-HT1A derivatives with modest 5-HT reuptake site affinity at best, and some compounds exhibited moderate 5-HT1A affinity, and some compounds had high affinity for thea1 receptor over the 5-HT1A affinity. So these compounds have no characters of multi-mechanisms and lower onset of action.Three series of compounds with the purpose of improvement on the two disadvantages were designed and synthesized. They consisted of anlogs of 2-(2- methoxyphenylsulfany)benzylamines (64), derivatives of thiopheny or benzo[b] thiophenyl-piperazines (13) and anlogs of duloxetine-piperazines (15). Selectivity of synthetic routes, procedure and results and discussion of each series of compound were discussed. The structures of all target compounds were identified by MS, 1H NMR and 13C NMR.The target compounds were evaluated in vitro for their antidepressive activity by determining their affinity at the 5-HT1A receptors and 5-HTT . Compounds 11, 13, 39, 40, 41, 67, 68, 72, 73, 74, 75, 21, 36, 38 showed high affinity for 5-HT1A receptors and compounds 2, 3, 7, 8, 9, 10, 11, 12, 13, 19, 60 showed high affinity for 5-HTT. Two compounds 11, 13 exerted good antidepressive activity with dual mechanisms and be used lead compounds for further study.A simple and efficient method has been developed for stereoselective one-pot...