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.

Fate and Relationship of N-Methyl to Activity of Morphine 237 This material gelled in most organic solvents, but was recrystallized from about 5 1. of dioxane 3 times and once from 3.5 1. of chloroform to obtain white waxy crystals, m.p. 120-122°. Other close analogs showed the same tendency to gel in most organic solvents at conventional concentrations.Acknowledgments.-We are grateful to Dr. D. B. Seeley for the fermentative preparation of the epoxy-succinic acid, to Dr. S. Y. P'an for measuring hypnotic activities, to Joseph Kaiser for toxicity determinations, to Dr. Arthur English for the antifungal tests, and to Charles Scott for technical assistance. Insecticide tests were done at the Wisconsin Alumni Research Foundation.

No abstract

Rabbit psoas muscle fibers, extracted in 50% ( w / v ) glycerol for 20 hours, concentrate up to 300 pmol calcium per gm protein when placed in a suitable electrolyte environment a t pH 6.5 containing ATP and 47Ca in the form of a Ca/EGTA metal buffer system. This property is retained at [Ca++] down to 2 x 10-8 M, the lowest studied. The kinetics of Ca pickup are consistent with a mathematical model based on diffusion of Ca as the rate-limiting factor. The pickup is dependent upon ATP and is increased by inclusion of CP or PEP. It is promoted by oxalate, fluoride, phosphate and pyrophosphate, which share the property of forming relatively insoluble calcium salts. Ability to concentrate calcium disappears on prolonged extraction in glycerol and after preincubation with desoxycholate.These properties are similar to those previously described for a granular fraction of muscle homogenates, and it is concluded that both are probably attributable to functional remnants of sarcoplasmic reticulum.