COMPARATIVE PROPERTIES OF SIX PHENETHYLAMINES, WITH OBSERVATIONS ON THE NATURE OF TACHYPHYLAXIS

¹ Research Laboratories, Parke, Davis & Co., Detroit 32, Michigan

1. The hydrochlorides of phenethylamine, its alpha- and beta-methylated derivatives, and the three corresponding N-methyl compounds were studied along with l-ephedrine in phenobarbitalized, atropinized dogs. Racemic forms were used where asymmetry occurred in the former six.

2. Average pressor potency (46-500µgm./kgm. dose level) on a molecular basis ranged within the same order of magnitude for the 7 compounds. The beta-methylated compounds were significantly less potent than the others.

3. Intravenous nasal-paranasal decongestant action (46-178 µgm./kgm. level) was recorded volumetrically with vago-sympathetic nerves cut. Decongestant efficiency was defined as the ratio of decongestant potency to pressor potency as determined against respective epinephrine scales from a common set of injections—an efficiency index with epinephrine set at unity. The parent amine and its N-methyl derivative were least efficient (significantly less than epinephrine), the beta-methylated intermediately, and the alpha-methylated most. In general, the primary amines were more efficient than the secondary. Inferences concerning nasal vasoconstrictor efficiency can be made with reservations.

4. Durability of action was measured in terms of time from beginning of effect until recession to hall-value. Its ratio to the same measure of the equipressor epinephrine response was termed the relative duration and was satisfactorily independent of dose level. Tachyphylaxis was studied systematically by repeated injections at decreasing time intervals of approximately pressor-equivalent doses (174-571 µgms./kgm.). The non-chain-methylated amines were least, the beta-methylated amines intermediately, and the alpha-methylated compounds most durable and tachyphylactic. l-Ephedrine was somewhat less durable and less precipitously tachyphylactic than the non-hydroxylated isopropylamines.

5. The tachyphylactic responses were found to fit with quantitative precision the hypothesis that they represent successive (more or less overlapping) stages of cumulative normal probability of receptor-point occupation by the agent, according to the logarithm of its cumulative concentration. Tachyphylaxis and self-potentiation seem to an important extent to be complementary phenomena, critically dependent upon the dose or initial probit-effect level, the steepness of the log. dose-probit effect curve (compactness of probability range of agent-receptor engagement), the rate of disposal of the agent, the time interval between injections, and the number of injections made. The over-all level of the function being cumulatively influenced by the agent may more or less completely return to the initial between injections, as in the case of the vigorously compensated cardiovascular system as a whole, or may not, as in the vascular bed of the neurally isolated nasal mucosa of the present experiments.