The actions of several meta-substituted N-ethylamphetamines on the release, uptake and catabolism of biogenic amines were investigated in vitro in two regions of rat brain. Each of the compounds released 3H-norepinephrine from chopped cerebral cortex, and 3H-dopamine and 3H-5-hydroxytryptamine from chopped corpus striatum. Stepwise multiple linear regression analyses indicated that the potencies (EC50 values) with which the compounds released 3H-norepinephrine were inversely related (r = 0.94) to the size of the meta substituent. Addition of substituent lipophilic or electronic effects to the regression equation did not greatly improve the correlation. However, the maximal release of 3H-norepinephrine produced by these compounds was directly related only to substituent lipophilic effects (r = 0.95). The potencies and maxima with which the compounds released 3H-dopamine or 3H-5-hydroxytryptamine and the potencies with which the compounds inhibited the uptake of the 3H-amines were not correlated with substituent size, lipophilicity or electronegativity. Variations in meta substituent also altered the degree to which the release 3H-amines were metabolized by monoamine oxidase. Multiple linear regression analyses indicated that for each of the 3H-amines, the maximal percent increase in 3H-deaminated metabolites produced by the drugs was directly correlated only with substituent size (r = 0.85, 0.89 and 0.95 for 3H-norepinephrine, 3H-dopamine and 3H-5-hydroxytryptamine, respectively). Comparisons among the potencies with which compounds released the various 3H-amines indicated that, in general, as substituent size increased, the compounds became relatively less potent in releasing 3H-catecholamines and relatively more potent in releasing 3H-5-hydroxytryptamine. Thus, these studies indicate that variations in the meta substituent group of N-ethylamphetamine derivatives determine the affinity of the derivatives for norepinephrine nerve endings and the relative affinities of the derivatives for norepinephrine, dopamine and 5-hydroxytryptamine nerve endings.