Pharmacology of lortalamine, a new potent non-tricyclic antidepressant

The new substance (+/-)8-chloro-1,2,3,4,10,10a-hexahydro-2-methyl-4a,10-(iminoethano )-4aH -[1]benzopyrano[3,2-c]pyridin-12-one (4a alpha,10 alpha,10a alpha) (lortalamine, LM 1404) is compared with imipramine in a series of pharmacological and biological tests. Lortalamine antagonises in a dose-related manner reserpine-induced ptosis and hypothermia, and is far more potent than imipramine in this regard. The compound potentiates yohimbine toxicity in mice and, in the anesthetized dog, diminishes the tyramine pressure response while increasing the response to norepinephrine. These results would indicate the capacity for lortalamine to act as a norepinephrine uptake inhibitor, and indeed, lortalamine is more potent than imipramine in inhibiting norepinephrine uptake by rat brain cortex slices. Lortalamine does not inhibit serotonin uptake by rat midbrain slices and neither interferes with 5-hydroxytryptophan and p-chloroamphetamine in mice. The interference with the dopaminergic system seems to be slight or even negligible, since the compound does not interfere with apomorphine or amphetamine in mice; moreover, dopaminergic uptake by rat striatum synaptosomes is inhibited only at very high concentrations. Lortalamine does not modify norepinephrine release, MAO activity nor behaviour of mice. Contrary to tricyclic antidepressants, lortalamine is devoid of anticholinergic and antihistaminic properties. The vegetative and cardiovascular effects as studied in the anesthetized dog are either absent or very slight. In particular, heart conduction is far less impaired in comparison to imipramine, which correlates with the absence of local anesthetic properties of the product.