A PHARMACOLOGIC STUDY OF ORTHO-METHOXY-beta-PHENYLISOPROPYL METHYLAMINE HYDROCHLORIDE, AND THIRTEEN RELATED METHOXY ANALOGUES

¹ Research Laboratories, The Upjohn Company, Kalamazoo, Michigan

In the study of a large series of phenyl propylamines several members of the group were found to possess greater bronchodilator activity than ephedrine with little or no pressor action. According to stability and activity the methoxyphenylisopropylamines seemed most interesting. The intravenous toxicities, pressor actions, and bronchodilator properties of 14 of these amines are reported. Ortho-methoxy--phenylisopropyl methylamine hydrochloride (‘Orthoxine’), because of its relatively high activity and low toxicity, was investigated further with the following results:

1. In perfusion experiments with isolated lungs using pilocarpine, histamine, or acetyicholine as the constrictor agents, ‘Orthoxine’ was found to be on the average a much more effective agent than ephedrine for relieving bronchoconstriction. Against pilocarpine and histamine it is more than twice as effective as ephedrine and about 1/5 to 1/20 as effective as epinephrine.

2. When tested for activity in relieving intestinal smooth-muscle spasms, using isolated strips of jejunum or ileum, ‘Orthoxine’ was found to be 4 to 8 times as effective as ephedrine against the spasmogenic agents, histamine, acetylcholine and barium chloride. Compared to epinephrine, ‘Orthoxine’ is about 1/10 as effective a barium chloride antagonist. In quieting the normal contractions of the unstimulated intestinal muscle, ‘Orthoxine’ is 5 times as effective as ephedrine. On the non-pregnant uterus, ‘Orthoxine’ is only 1/2 as active as ephedrine in stimulating the muscle to contraction.

3. ‘Orthoxine’ produces little or no pressor response, possessing at most in this regard 1/2000 the activity of epinephrine and 1/8 that of ephedrine. Four times as much ‘Orthoxine’ as ephedrine must be administered to normal dogs to produce the bradycardia characteristic of the latter.

4. Inhibition of histamine bronchoconstriction, vasodepression, and smooth-muscle spasm shows that ‘Orthoxine’ possesses antihistaminic properties. The intestinal smooth-muscle tests indicate that the order of activity is 1/20 that of ‘Benadryl’ but is much greater than that of ephedrine.

5. Except for a higher intravenous toxicity, acute and chronic toxicity tests in rats, rabbits and guinea pigs show that the toxicity of ‘Orthoxine’ is of the same order as that of ephedrine. No pathological changes were found after the continuous daily administration of either 20 or 100 mgm. per kgm. doses for 21 days.

6. The pharmacological properties of ‘Orthoxine’ suggest that it may be of value in the treatment of asthma, for which it is presently being clinically evaluated.