Norepinephrine uptake sites in cardiac tissue. Lack of affinity of 6-hydroxynorepinephrine and related compounds

Abstract

The effects of a series of phenethylamines and the corresponding phenethanolamines on (i) rate of uptake of radioactive norepinephrine into cardiac tissue in vivo and (ii) the rate of efflux of radioactive norepinephrine from prelabeled cardiac storage sites have been determined. The results indicate that m- and p-hydroxuphenethylamines and the corresponding phenethanolamines have high affinities for uptake into cytoplasm and storage vesicles of noradrenergic terminals in the heart. o-Hydroxyphenethylamines such as 2-hydroxyphenethylamine and 2,4,5-trihydroxyphenethylamine (6-hydroxydopamine) also have moderate to high activity as inhibitors of norepinephrine uptake and as releasing agents for norepinephrine, but o-hydroxyphenethanolamines such as 2-hydroxyphenethanolamine, 2,5-dihydroxyphenethanolamine, and 2,4,5-trihydroxyphenethanolamine (6-hyproxynorepinephrine) have little or no activity as inhibitors of uptake or as releasing agents. 2,6-Dihydroxyphenethylamines have little or no activity as inhibitors of uptake or as releasing agents. The results are consonant with significant binding of the gauche conformers of 2-hydroxyphenethylamines to uptake sites. Such conformers would be preferred because of stabilization by hydrogen bonding between nitrogen and phenolic oxygen. Apparently a hydrophobic region of the site prevents binding of such stabilized gauche conformers of 2-hydroxyphenethanolamines and 2,6-dihydroxyphenetylamines.