Structural Characteristics for Inhibition of [3H] Norepinephrine Uptake into Rat Brain Synaptic Vesicles by Beta-Carboline, Indolealkylamine, Phenethylamine and n-Alkylamine Derivatives

The abilities of four different classes of monoamines to inhibit uptake of [ 3 H]norepinephrine into rat brain synaptic vesicles were evaluated. Compounds from all four produced competitive inhibition with the following general order of potency: β-carbolines> indolealkylamines> phenalkylamines> n -alkylamines. The minimal structural features required for uptake inhibition consisted of an amino nitrogen separated from a hydrophobic moiety by at least a 2-carbon bridge. The most important substituent group was the 5-hydroxyl group for indolealkylamines, the p-hydroxyl group for the phenalkylamines or the 7-methoxyl group for the β-carbolines. Linear alkylamines produced a dual effect, with competitive inhibition of uptake at low concentrations and detergent-like actions predominating with increasing chain length or with high concentrations. Analysis of the details of structure-activity relationships indicates that the characteristic of the amine transport site of brain catecholamine vesicles differs substantially from that of adrenomedullary vesicles.