Depression　is　a　chronic,　severe,　and　often　life-threatening　neurological　disorder.　It　not　only　causes　depression　in　patients　and　affects　daily　life　but,　in　severe　cases,　may　lead　to　suicidal　behavior　and　have　adverse　effects　on　families　and　society.　In　recent　years,　it　has　been　found　that　sub-anesthetic　doses　of　ketamine　have　a　rapid　antidepressant　effect　on　patients　with　treatment-resistant　depression　and　can　significantly　reduce　the　suicidal　tendencies　of　patients　with　major　depressive　disorder.　Current　studies　suggest　that　ketamine　may　exert　antidepressant　effects　by　blocking　NMDAR　ion　channels,　but　its　anesthetic　and　psychotomimetic　side　effects　limit　its　application.　Here,　we　report　efforts　to　design　and　synthesize　a　novel　series　of　ketamine　derivatives　of　NMDAR　antagonists,　among　which　compounds　23　and　24　have　improved　activity　compared　with　ketamine,　introducing　a　new　direction　for　the　development　of　rapid-acting　antidepressant　drugs.　©　2024　by　the　authors.