Structure-activity relationships between meta-substituted N-ethylamphetamines and isolated guinea-pig atrial rate.

The effects of N-ethylamphetamines (NEAs) substituted at the meta position of the phenyl ring with H, F, Cl, Br, I, CF3, CH3O, NO2, or OH were examined on the rate of spontaneously beating isolated guinea-pig atria. All compounds, with the exception of meta-iodo NEA and meta-trifluoromethyl NEA (fenfluramine), increased atrial rate to varying degrees, as determined in cumulative concentration-response curves that included concentrations which were ineffective through those which decreased rate. Multiple linear regression analyses indicated that the respective maximum increases in atrial rate produced by these compounds were inversely related to the meta-substituted steric factor (size); neither hydrophobic nor electronic substituent effects contributed significantly to the relationship. In atria obtained from guinea pigs pretreated with the monoamine oxidase inhibitor, pargyline (100 mg/kg, 4 hours pretreatment), the stimulant effects of these compounds were markedly potentiated and were again inversely related only to substituent size. In addition, after pargyline, meta-iodo NEA and fenfluramine greatly stimulated the atria. In atria. In atria obtained from guinea pigs which had been administered reserpine (5 mg/kg, 24 hours pretreatment), none of the compounds except meta-hydroxy NEA increased atrial rate. The interactions of pargyline and reserpine pretreatment with the actions of these NEA congeners suggest that all are indirectly acting sympathomimetic amines, except the hydroxylated compound, which is mixed-acting.