Inhibition of epinephrine and metaraminol uptake into adrenal medullary vesicles by aralkylamines and alkylamines

Two amine uptake mechanisms appeared to operate in isolated adrenal medullary storage vesicles; one site had a high affinity for epinephrine (Km ∼- 30 ωM) and low capacity (Umax ∼- 20 nmoles/100 ωg of endogenous catecholamines), while the other had a low affinity (Km {reversed tilde equals} 2 mM) and a higher capacity (Umax {reversed tilde equals} 130 nmoles). The low affinity site was non-specific and did not display competitive inhibition by agents which affected the high affinity, stimulated transport system. The high affinity system was inhibited in a purely competitive fashion by a variety of indoleamines and phenethylamines. but the two classes of compounds displayed different structure-activity relationships. Substitution on the α-carbon decreased the abilities of indoleamines to inhibit stimulated epinephrine uptake, but enhanced activity of phenethylamines. Ring hydroxylation reduced, and methoxylation eliminated, the inhibitory activity of tryptamine, but the same substituents markedly enhanced the activity of phenethylamines. Studied of compounds with restricted side-chain conformation indicated that a condensed structure favored activity in indoleamines, while an extended chain enhanced inhibition by phenethylamines. Linear alkylamines of 5- or 6-carbon length were also able to inhibit active epinephrine uptake. None of the agents inhibited the non-stimulated uptake component of metaraminol, which uses primarily the low affinity system. These data suggest that while indoleamines and phenethylamines do compete with epinephrine for attachment to the high affinity transport site in the vesicle membrane, the point of interaction is probably solely at the locus which binds the amine nitrogen; the remainder of the two types of molecule probably bind to at least two different sites adjacent to the N-binding area. © 1975.

Duke Scholars

Author Theodore Alan Slotkin Pharmacology & Cancer Biology

Author Frederic J. Seidler Pharmacology & Cancer Biology