Abstract

The immediate and long-term effects of the six isomeric trihydroxyphenethylamines and 2,3,4,5-tetrahydroxyphenethylamine on the uptake and release of [³H]norepinephrine from storage sites in cardiac tissue of the mouse in vivo have been compared. In addition, the rate of autoxidation of these amines has been measured. The order of potency of the various isomers for inhibition of uptake is: 3,4,5 = 2,4,5 = 2,3,4 > 2,3,4,5 > 2,3,5 >> 2,4,6 > 2,3,6; the order of activity for release is: 2,4,5 = 3,4,5 > 2,3,5 > 2,3,4 > 2,3,4,5 >> 2,4,6 >> 2,3,6. The α-methyl derivative of the 2,4,5-isomer (6-hydroxydopamine) is nearly twice as effective as the parent amine as a releasing agent , while the N,N-dimethyl derivative is completely inactive. The order for rate of autoxidation is: 2,3,4,5 >> 2,3,5 = 2,3,6 = 2,4,5 = N,N-dimethyl-2,4,5 > 2,3,4 > 3,4,5 >> 2,4,6. Only the 2,4,5-isomer, the α-methyl derivative of the 2,4,5-isomer, the 2,3,5-isomer, and the 2,3,4,5-tetrahydroxyphenethylamine cause long-term reduction in the cardiac uptake of [³H]norepinephrine. These results support the hypothesis that neurodegeneration can only be initiated when a critical intraneuronal concentration of a readily autoxidizable amine is attained as a direct result of an affinity of the amine for the active uptake process at the neuronal membrane.