Blockade of amine depletion by nisoxetine in comparison to other uptake inhibitors.

Nisoxetine, 3-(o-methoxyphenoxy)-3-phenyl-N-methyl-propyl-amine, is a new inhibitor of norepinephrine uptake. Nisoxetine antagonized 6-hydroxydopamine-induced depletion of norepinephrine in mouse heart with an ED50 of 0.9 mg/kg but had no effect on p-chloroamphetamine-induced depletion of serotonin in mouse brain at doses up to 32 mg/kg. Using the antagonism of these depleting agents to estimate inhibition of uptake into noradrenergic and serotoninergic neurons, we compared nisoxetine to several known amine uptake inhibitors. The order of effectiveness in antagonizing 6-hydroxydopamine action was protriptyline greater than desmethylimipramine greater than EXP 561 greater than nisoxetine greater than nortriptyline greater than chlorpheniramine greater than desmethylchlorimipramine greater than imipramine greater than doxepin greater than amitriptyline greater than chlorimipramine, with fluoxetine and its N-demethylated metabolite (103947) having no effect. In blocking p-chloroamphetamine, the order of effectiveness was EXP 561 greater than fluoxetine greater than 103947 greater than chlorpheniramine greater than chlorimipramine, with desmethylchlorimipramine, protriptyline, and nortriptyline having marginal effects and nisoxetine and the other drugs no effect at the highest dose tested, 32 mg/kg. Nisoxetine is thus one of the more potent and specific inhibitors of norepinephrine uptake, differing remarkably from fluoxetine to which it is related structurally.