Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by .alpha.-amino acid esters of phenethyl alcohols

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Abstract
A series of .alpha.-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline [norepinephrine] and 5-hydroxytryptamine in mouse brains. Some of the compounds are potent and very selective in blocking the 5-hydroxytryptamine uptake, as evidenced by biochemical data and behavioral tests. The most promising agent, alaproclate [2-(4-chlorophenyl)-1,1-dimethylethyl 2-aminopropanoate hydrochloride, was selected for further studies as a potential antidepressant agent. A discussion on structure-activity relationships (SAR) is given. In an attempt to explain the selective action on the mechanism of 5-hydroxytryptamine uptake by the new inhibitors, their structures are compared with those of the two neurotransmitters. From the tentative pharmacophore and conformations of transmitter (5-HT) and inhibitor (alaproclate) derived from SAR, a hypothetic carrier site for 5-HT uptake is deduced in terms of geometry and electronic properties.
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