Scaffold Hopping Toward Agomelatine: Novel 3 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents

摘要

A scaffold-hopping strategy toward Agomelatine based on in silico screening and knowledge analysis was employed to design novel antidepressant agents. A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (>6a-1, >6a-2, >6a-9) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound >6a-1 also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects in vivo. The forced swim test (FST) results revealed that compound >6a-1 remarkably reduced the immobility time of rats and the open field test (OFT) results indicated a better general locomotor activity of the rats treated with compound >6a-1 than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound >6a-1 can significantly reduce PC12 cell apoptosis by up-regulation of GSH and down-regulation of ROS in corticosterone-induced lesion of PC12 cells. Meanwhile, the down-regulation of calcium ion concentration and up-regulation of BDNF level in PC12 cells may account for the neuroprotective effects. Furthermore, compound >6a-1 can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data in vivo indicated compound >6a-1 exhibited less hepatotoxicity than Agomelatine.