The effects of N-ethylamphetamines substituted at the meta position of the phenyl ring with H, F, Cl, Br, I, CF3, CH3O, NO2 or OH were examined on locomotor activity in mice. With the exception of meta-CF3-N-ethylamphetamine (fenfluramine), all compounds stimulated locomotor activity to varying amounts as determined in dose-activity curves that included doses which were ineffective through doses which either decreased activity relative to lower doses or were lethal. Multiple linear regression analyses indicated that the extent to which these compounds increased locomotor activity was inversely related to meta-substituent steric effects (size, r equal to 0.90), whereas hydrophobic and electronic substituent effects did not contribute significantly to this relationship. In mice pretreated with pargyline (100 mg/kg, 4 hours), the stimulant effects of these compounds were potentiated and again were inversely related only to substituent size (r equal to 0.77). In reserpine-pretreated mice (5 mg/kg, 24 hours), no relationship was obtained with size, hydrophobic or electronic effects individually or together. Reserpine pretreatment eliminated the rate-increasing effects of the iodinated and hydroxylated derivatives but not those of the other compounds. Pretreatment with alpha-methyl-para-tyrosine (100 or 320 mg/kg, 1 hour) caused a dose-related abolition of N-ethylamphetamine-induced increases in acitivity. These data suggest that the amphetamine derivatives of the present study act indirectly, probably through release of catecholamines.