Synthesis and biological evaluation of magnolol derivatives as melatonergic receptor agonists with potential use in depression

摘要

Depression is associated with high mortality and morbidity rates worldwide. By our random screening, it was first revealed that 23 magnolol derivatives were synthesized followed byin?vitroandin?vivoevaluation of their antidepressive potential. Compound7cwas found to be the most promising compound, with EC50values of 396.5 and 383.0?μM agitating on MT1and MT2receptors, respectively. Additionally, we carried outin?vivoexperiments to confirm the efficacy and safety of compound7c; the compound was found to be orally bioavailable and highly effective, leading to a significant reduction of immobility time in a mouse model of depression (forced swimming test and tail suspension test); the acting mechanism was explored by determining its effect on the levels of monoamine neurotransmitters and their metabolites in different mice brain regions; the acute toxicity study showed that the 50% lethal dose (LD50) of7cwas higher than 2000?mg/kg, p. o. A total of 25 metabolites of7cwere identified, including 5 metabolites in phase I and 20 metabolites in phase II. Altogether, these results indicate that magnolol derivative7cis a promising lead compound for the development of a new chemical class of antidepressant drugs.