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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.

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