Cytochrome P-450 oxidizes N-hydroxyphentermine (MPPNHOH) by an indirect pathway involving superoxide. The chemical details of this oxidation, in which N-hydroxyphentermine is converted to 2-methyl-2-nitro-1-phenylpropane (MPPNO2), have been elucidated by examining the interaction of MPPNHOH with superoxide in aqueous and organic solvents. The role of peroxide, hydroperoxy radicals, and oxygen in the reaction was also examined. The results indicate that superoxide itself is oxidizing MPPNHOH to a nitroxide that disproportionates to MPPNHOH and 2-methyl-2-nitroso-1-phenylpropane (MPPNO). MPPNO is then oxidized to MPPNO2 by O2 or hydroperoxide. Two possible mechanisms for the superoxide oxidation were considered, a proton abstraction and a hydrogen atom abstraction. Stoichiometric and oxygen evolution studies favor the hydrogen abstraction pathway.
The mechanism of the formation of the complexes between various nitrosobenzenes and cytochrome P-450 has been investigated. We have observed the formation of these complexes by a new and, as yet, undescribed route. Nitrosobenzene (NOB) itself reacts with cytochrome P-450 in the iron(III) state, in the absence of any exogenous reducing agent, to produce the iron(II)-NOB complex. Apparently, NOB is a ligand that is capable of causing the spontaneous autoreduction of the iron. The reduction of the iron may occur via ligand-induced oxidation of the axially bound thiolate of cytochrome P-450.
Eight benzylamine analogues of bretylium were synthesized, including N-(2-chloroethyl)-N-ethyl-2-methylbenzylamine (5), and evaluated as inhibitors of accumulation of norepinephrine and dopamine in rat brain homogenates. All compounds gave an I50 value (concentration of inhibitor that causes 50% reduction in control accumulation) considerably lower against norepinephrine in cortex that against dopamine in striatum. High potency (low I50) and high specificity (preference for inhibition of norepinephrine transport compared to dopamine transport) are associated with a (2-chloroethyl) moiety, tertiary amino center, and ortho substitution of the aromatic function in the benzylamino group. 5 also inhibited the uptake of norepinephrine in rabbit aorta, indicating its effect against the uptake process in general. Cocaine protects against the effects of 5 in coincubation studies when compared to the appropriate controls, indicating that 5 acts at or close to the site of action of cocaine which is thought to be the uptake carrier site.
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