Effect of deuteration of N--CH3 group on potency and enzymatic N-demethylation of morphine.

Substitution of deuterium for the N-methyl hydrogens of morphine produced a significant reduction in the potency and lethality of morphine in mice regardless of the route of administration. There was no effect on the time of onset, maximal effect, or duration of action. N-demethylation by rat liver microsomal enzymes was characterized by a smaller reaction rate constant, a higher energy of activation, and a larger Michaelis constant with respect to the deuterated morphine. These findings indicated that deuteration of the N-methyl group of morphine not only caused reduction in potency, but also a reduction in the rate of oxidative N-demethylation, and a distinct weakening of the binding to the enzyme active centers.