Inhibitors of neuronal monoamine uptake. 2. Selective inhibition of 5-hydroxytryptamine uptake by alpha-amino acid esters of phenethyl alcohols.
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.
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D000431:Ethanol / Q000031:analogs & derivatives*; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D009184:Mydriatics / Q000138:chemical synthesis; D009638:Norepinephrine / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D009184:Mydriatics; D012701:Serotonin; D000431:Ethanol; D010626:Phenylethyl Alcohol; D009638:Norepinephrine