Design, Synthesis And Evaluation Of Antidepression Activity Of Benzodioxane Derivatives

Depression is a severe, recurring, chronic and potentially life-threatening illness. Since the introduction of the first generation of antidepressant drugs such as tricyclic antidepressants and monoamine oxidase inhibitors, serotonin (5-HT) and norepinephrine were known as important drug targets of the treatment of depression. Tricyclic antidepressants and monoamine oxidase inhibitors have been largely replaced in clinical use in most parts of the world by newer antidepressants which typically have more favorable side-effects profiles such as the selective serotonin reuptake inhibitors, noradrenaline reuptake inhibitors, and serotonin and noradrenaline reuptake inhibitors. However, there are some limitations associated with the use of selective serotonin reuptake inhibitors including a long onset of action and moderate patient response. Thus, the discovery of novel antidepressants need to be improved the efficacy in treatment resistant patients, to shorten the onset of action, to reduce adverse effects.In this paper, the literatures about new achievements of antidepressants were reviewed. According to the monoamine hypothesis of depression, three series of derivatives were successfully designed, synthesized and screened. The structures of new compounds were confirmed with Mass Spectrometry and Nuclear Magnetic Resonance.Compounds were evaluated in vitro to determine their affinity for the5-HT1A,5-HT2A,5-HT2C、5-HTT, α1、α2and D2receptors.2,3-Dihydrobenzo[b][1,4]dioxin-piperidine-2,6-dione(pyrrolidine-2,5-dione) and benzoxazole(benzothiazole)-2,3-dihydro-benzo[b][1,4]dioxine derivatives exhibited high affinities for the5-HT1A and5-HT2A receptors showed high affinity for the5-HT1A and5-HT2A;2,3-Dihydrobenzo[b][1,4] dioxin-and indolealkylamine derivatives exhibited high binding affinities at the5-HT1A receptor and serotonin transporter.Antidepressant-like activities of36compounds were screened using the tail suspension and forced swim tests in mice. Preliminary results indicated11compounds showed a marked antidepressant-like activity, and compound55exhibited greater antidepressant efficacy than fluoxetine. Compounds55displaying remarkable activity was selected for the acute toxicity, the LD50values of nine compounds exceeded365mg/kg. Compound55was selected based on its in vitro profile for in vivo characterization. Intravenous administration of compound55to rats (10mg/kg) resulted in detectable plasma levels (ti/2=4.1h), and oral administration of compound55to rats (30mg/kg) resulted in a ti/2of5.0h. The area under the curve value of compound55was5200μg·h/L after intravenous administration versus6090μg·h/L after oral administration. The Cmax value after oral dosing was591μg/L, and after intravenous administration was1660μg/L. The Tmax value after oral dosing was4.7h. The bioavailability of compound55was39%in rat.The tail suspension test and forced swim test revealed that compound55possessed potential antidepressant activity. Moreover, compound55exhibited acceptable pharmacokinetic properties and that showed relatively moderate inhibition against HERG. Our preliminary results are sufficiently promising to warrant that compound55is being used a development candidate for promising antidepressant.