Nontricyclic antidepressant agents derived from cis- and trans-1-amino-4-aryltetralins

Abstract

The need for drugs that lack the obtrusive and limiting side effects of the tricyclic antidepressants prompted the search for agents with greatly enhanced selectivity for specific mechanisms believed to be essential for antidepressant efficacy. The potential role of derangements of 5-HT [5-hydroxytryptamine] pathways in the etiology of depression was long suspected and gave impetus to the development of newer compounds that accentuate inhibition of serotonin reuptake. This paper presents structure-activity relationships for a series of cis-1-amino-4-(substituted-aryl)tetralins, which are surprisingly potent and selective inhibitors of serotonin uptake in in vitro models. These compounds are pharmacologically distinct from corresponding members of the trans series, which also potently block uptake of dopamine and norepinephrine in rats. The activity in both cis and trans series is stereospecific, being restricted to the cis-(1S,4S) and the trans-(1R,4S) enantiomers.