THE PHARMACOLOGIC ACTION OF SOME ANALOGS OF 1-(3,4-DIHYDROXYPHENYL)-2-AMINO-1-BUTANOL (ETHYLNOREPINEPHRINE)

¹ Pharmacology Section of the Sterling-Winthrop Research Institute, Rensselaer, New York

1. The pharmacologic actions of N-isopropyl (WIN 3046), N-cyclopentyl (WIN 515) and N-cyclohexyl (WIN 713) analogs of 1-(3,4-dihydroxyphenyl)-2-amino-1-butanol (ethylnorepinephrine, Butanefrine) on bronchial tonus, blood pressure, heart rate, intestinal and uterine tonus and activity of the central nervous system, as well as systemic toxicity, have been investigated in comparison with those of 1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol (Isuprel), epinephrine and l-arterenol.

2. These ethylnorepinephrine derivatives lower blood pressure of barbitalized dogs, WIN 713 being distinctly less active than either WIN 3046 or WIN 515. The latter derivatives are about equally active but distinctly less active than Isuprel.

3. The ethylnorepinephrine derivatives increase the heart rate of barbitalized dogs but are considerably less effective than Isuprel. WIN 3046 and WIN 515 are equally active and more potent than ethylnorepinephrine or WIN 713.

4. WIN 3046 and WIN 515 are much more effective bronchodilator agents than WIN 713 or ethylnorepinephrine. Their potency approaches that of Isuprel. In the anesthetized dog, Isuprel is approximately ten times more bronchodilator but 40-80 times more effective in increasing the heart rate. These ratios suggest that cardiac stimulation, as an undesirable side effect, would be less likely to occur with therapeutic doses of WIN 3046 and WIN 515 than with Isuprel.

5. WIN 3046, WIN 515 and WIN 713 exert a weak inhibitory action on the isolated guinea pig intestine. Isuprel is more than 1000 times more potent; epinephrine and l-arterenol are intermediate in potency. WIN 3046 and WIN 515 are distinctly more potent than WIN 713 or ethylnorepinephrine on the intestine in situ in barbitalized dogs. Epinephrine and l-arterenol are slightly more effective than Isuprel and many times more effective than ethylnorepinephrine and its analogs on the intestine in situ.

6. WIN 3046, WIN 515, epinephrine and Isuprel are strong inhibitors, of comparable potency, on the isolated guinea pig uterus stimulated with pituitrin. Ethylnorepinephrine, WIN 713 and l-arterenol are much weaker inhibitory agents.

7. WIN 3046, WIN 515, WIN 713 and ethylnorepinephrine do not increase the spontaneous activity of rats, as determined by the "jiggle-cage" method.

8. The ethylnorepinephrine derivatives have an acute intravenous toxicity (mouse) comparable to that of Isuprel and are much less toxic than epinephrine or l-arterenol.

9. Evidence is presented which suggests that the structural requirements for myocardial stimulation differ from those favorable for sympathetic excitatory or inhibitory action.