Tridihexethyl Chloride

cf. CA 56, 7934h.Triethylcholine chloride (I) (15 mg./kg.) was injected intravenously into each of 5 rabbits. Between 25 and 40 min. after injection the rabbits lost the strength to right themselves after 2-10 trials.By 100 min. after injection, they again responded to 20 trials.On subsequent days the same doses of I were administered and at the height of the ensuing muscular weakness edrophonium (II) (1 mg./kg.), neostigmine (III) (0.25 mg./kg.), or choline (IV) (5 mg./kg.) was injected intravenously.The rabbits were atropinized before III or IV was administered.II caused a striking but temporary improvement in muscular strength, III a slightly greater and longer lasting improvement which merged with the spontaneous recovery, and IV a return to almost normal activity within 5-10 min.In cats under chloralose anesthesia clonic contractions of the muscle were elicited by stimulation of the motor nerve with supramaximal shocks of 100 microsec. duration at a frequency of 10/sec. for 1 sec. every 10 sec.To hasten the onset of transmission failure, 12 tetani, each of 1-sec. duration and 100/sec. frequency were delivered within the space of 1 min. after 10 min. had elapsed since the injection of I (100 mg./kg.).In the normal muscle such high frequency stimulation did not cause appreciable fatigue, but after I the subsequent test responses were markedly depressed.This degree of transmission failure was maintained at a constant level for about 90 min. providing the stimulation was delivered at regular intervals throughout.After this period gradual recovery of the contractions occurred.Recovery was hastened by short periods of rest.Intravenous injections of II, III, or IV reversed the transmission failure.III produced about the same degree of antagonism as II but its duration of action was considerably longer.An injection of IV caused complete restoration of contractions and this effect was persistent.As in myasthenia gravis, II and III caused a marked improvement in the strength of muscles depressed by I.Of 25 analogs of choline examined I was the best.Some bisquaternary compounds were also studied.Those with Me groups attached to the quaternary N possessed a depolarizing action, while those with large groups on the quaternary N had a curarelike action; compounds with groups intermediate in size behaved like I.Chronic toxicity of I in dogs, cats, and rabbits produced no cumulative paralyzing action.