The interaction of sympathomimetic amines with the transport of 3H-noradrenaline (3H-NE), 3H-dopamine (3H-DA) and 3H-5-hydroxytryptamine (3H-5-HT) were investigated in rat hypothalamic (3H-NE) and striatal (3H-DA) and 3 H-5-HT) synaptosomes. Modifications in the phenylethylamine structure led to changes in activity towards biogenic amine uptake and release: (a) the introduction of a beta-OH group led to compounds less active in inhibiting uptake and stimulating release of 3H-NE, 3H-DA and 3H-5-HT, with the exception of 3H-NE release which was stimulated more by unlabeled 1-NE than by DA; (b) the introduction of phenolic-OH groups always led to compounds which were stronger uptake inhibitors and releasers of the three biogenic amines; (c) the alpha-methylation increased the potency towards uptake inhibition and release stimulation, with the exception of 3H-NE release: in fact, the releasing activity of phenylethylamine was suppressed by alpha-methylation; (d) the introduction of a -Cl group in the para position selectively potentiated the effects on 3H-5-HT uptake and release and generally depressed those on catecholamine transport.