In an attempt to evaluate the possible relationship between the neurotoxicity of 6-hydroxydopamine and the redox properties and electrophilic reactivity of the 6-hydroxydopamine-p-hydroquinone/p-quinone system, we have synthesized a series of 6-hydroxydopamine analogues in which the C4-hydroxy group is replaced with various electron-donating and electron-withdrawing substituents. With the aid of cyclic voltammetry, the formal oxidation potentials (E degrees ') for the p-hydroquinone/p-quinone redox couples and the rates of cyclization of the p-quinones to the corresponding p-iminoquinones were determined. As expected, electron-rich p-hydroquinones were easily oxidized to the p-quinones, which underwent cyclization slowly, whereas the oxidation of electron-poor p-hydroquinones required higher voltages and yielded p-quinones, which cyclized readily at pH 7.4. The neurotoxic potential of these compounds showed that in vivo destruction of noradrenergic terminals, as measured by inhibition of norepinephrine uptake by rat heart slices, occurred only with those analogues bearing electron-donating substituents. Potent neurotoxic properties were associated only with the 4-amino and 4-hydroxy derivatives, both of which form p-quinones, which do not cyclize readily at pH 7.4. These results support the thesis that the p-quinone derived from 6-hydroxydopamine may be an important species in the mediation of the neurodestruction caused by 6-hydrodopamine.