Structure--activity relations for the acceleration of efflux of noradrenaline from adrenergic nerves in rabbit atria by sympathomimetic amines.

Atria from reserpine-pretreated rabbits were exposed to pargyline to inhibit monoamine oxidase (amine oxidase (flavin-containing) EC 1.4.3.4) and subsequently incubated in (-)-[3H]noradrenaline to allow the cytoplasmic accumulation of amine in adrenergic nerves. The structure-activity relations for acceleration of efflux of cytoplasmic amine were examined. The most potent agents studied were (+)- and (-)-amphetamine, beta-phenethylamine, phentermine, and mephentermine. Ability to accelerate efflux was reduced by addition of phenolic hydroxyl groups, by phenolic methylation, by beta-hydroxylation, and by N-substitution. The structure-activity relations for acceleration of efflux differ notably from those for uptake, inhibition of uptake, or release of noradrenaline from adrenergic nerves, reported in previous studies. The ability and potency of a given phenethylamine derivative to accelerate the efflux of cytoplasmic noradrenaline is probably determined by such factors as the lipid solubility of the amine, the affinity of the amine for the uptake and efflux site(s) for noradrenaline, and competition for any reserpine-resistant intraneuronal binding sites.