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A series of 3, 4-dihydroisoquinoline compounds were selected for chemical synthesis and biological assessment. Three compounds (<jats:bold>6a-1<\/jats:bold>, <jats:bold>6a-2<\/jats:bold>, <jats:bold>6a-9<\/jats:bold>) demonstrated protective effects on corticosterone-induced lesion of PC12 cells. Compound <jats:bold>6a-1<\/jats:bold> also displayed low inhibitory effects on the growth of HEK293 and L02 normal cells and it was further evaluated for its potential antidepressant effects <jats:italic>in vivo<\/jats:italic>. The forced swim test (FST) results revealed that compound <jats:bold>6a-1<\/jats:bold> 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 <jats:bold>6a-1<\/jats:bold> than those with Agomelatine or Fluoxetine. Mechanism studies implied that compound <jats:bold>6a-1<\/jats:bold> 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 <jats:bold>6a-1<\/jats:bold> can increase cell survival and cell proliferation, promote cell maturation in the rat hippocampus after chronic treatment. The acute toxicity data <jats:italic>in vivo<\/jats:italic> indicated compound <jats:bold>6a-1<\/jats:bold> exhibited less hepatotoxicity than Agomelatine.<\/jats:p>","DOI":"10.1038\/srep34711","type":"journal-article","created":{"date-parts":[[2016,10,4]],"date-time":"2016-10-04T11:51:37Z","timestamp":1475581897000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Scaffold Hopping Toward Agomelatine: Novel 3, 4-Dihydroisoquinoline Compounds as Potential Antidepressant Agents"],"prefix":"10.1038","volume":"6","author":[{"given":"Yang","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haiyue","family":"Long","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zicheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangxue","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youfu","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,10,4]]},"reference":[{"key":"BFsrep34711_CR1","first-page":"181","volume":"515","author":"K Smith","year":"2014","unstructured":"Smith, K. 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