The effects of tandamine, a new potential antidepressant agent, on biogenic amine uptake mechanisms and related activities

Abstract

The effects of various thiopyrano [3,4-b]indoles and pyrano [3,4-b] indoles on norepinephrine (NE) and 5-hydroxytryptamine (5-HT) uptake were determined in mice. A thiopyranoindole, tandamine, ∗ ∗ 1-[2-(dimethylamino)ethyl]-9-ethyl-1,3,4,9-tetrahydro-1-methyl-thiopyrano [3,4–6]indole hydrochloride. was a potent inhibitor of [ 3H]NE uptake in the heart, being three times more active than desimipramine, and was relatively ineffective in potentiating the 5-hydroxytryptophan (5-HTP) behavioural syndrome. A pyranoindole and a thiopyranoindole blocked both [ 3H]NE and brain 5-HT uptake with activities greater than, or similar to imipramine. Structure-activity relationships for these two activities were determined. Tandamine was the most potent in antagonizing reserpine-induced hypothermia and the guanethidine-induced depletion of heart [ 3H]NE. The (−)enantiomer of tandamine exhibited greater activity in blocking NE and 5-HT uptake. The results indicate that tandamine and certain, of its congeners, differing chemically from the known tricyclic antidepressants, exert relatively selective stereochemical effects on NE and 5-HT uptake mechanisms. Such agents are potentially useful as antidepressants and as tools for further studies of the uptake mechanism and functional significance of NE and 5-HT.