Designing rapid onset selective serotonin re-uptake inhibitors. Part 1: Structure–activity relationships of substituted (1S,4S)-4-(3,4-dichlorophenyl)-N-methyl-1,2,3,4-tetrahydro-1-naphthaleneamine

A series of sertraline analogues 4–39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced Vd as a strategy to reduce Tmax and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced Vd leading to significantly shorter Tmax, in rat pharmacokinetic studies.