A series of alpha-amino acid esters of substituted phenethyl alcohols was prepared and tested as inhibitors of the neuronal reuptake of noradrenaline and 5-hydroxytryptamine. 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 (I, IV)], 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.

Alaproclate, a new specific 5-HT uptake inhibitor, was examined for its action on several receptors in the brain, for its action on the NA, DA and 5-HT uptake mechanisms in vivo and for its action on brain biogenic amine content. Alaproclate was practically devoid of action on a number of receptors as examined in binding studies in vitro: 5-HT, histamine-H1, alpha 1, -alpha 2-adrenergic and dopamine D2 receptors. Alaproclate had also a weak affinity for 3H-norzimeldine binding sites in contrast to imipramine. Unlike the tricyclic antidepressants alaproclate had a negligible action on muscarinic receptors and failed to block muscarinic induced stimulation in vivo. Contrary to clomipramine alaproclate failed to block NA uptake in vivo. Alaproclate was found to display a regional selectivity in blocking 5-HT uptake in vivo (measured with the H 75/12-method). The compound was most potent in the hippocampus and hypothalamus followed by striatum and cerebral cortex with a low potency in the spinal cord. The results are discussed in relation to a previously presented carrier site model for serotonin reuptake.

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