N,N ‐dialkyltryptamines inhibit plasma membrane and vesicular serotonin transport

Abstract

The plant hallucinogen N,N ‐dimethyltryptamine (DMT) has been used for religious and other purposes for many centuries. Over the past few decades, DMT has been reported in human brain, and pharmacological studies have shown that DMT binds to monoamine receptors. Recently, several N,N ‐dialkyltryptamines were reported to modify monoamine uptake and release in rat brain synaptosomes, indicating that these compounds also affect monoamine transporters. To further clarify the mechanism of action of hallucinogenic tryptamines, we synthesized DMT and several other N,N ‐dialkyltryptamines and tested them for their abilities to inhibit [ 3 H]5‐HT uptake via the plasma membrane serotonin transporter (SERT) and via the vesicle monoamine transporter (VMAT2). SERT transport was assayed in human platelets and VMAT2 uptake was assayed in Sf9 cells infected with a recombinant baculovirus expressing rat VMAT2. The compounds were also tested as inhibitors of [ 3 H]dihydrotetrabenazine (TBZOH) binding. Our results show that DMT and other N,N ‐dialkyltryptamines inhibit [ 3 H]5‐HT transport at SERT and VMAT2 at low micromolar concentrations. The K i for TBZOH binding/K i 5‐HT uptake ratios suggest that these compounds may act as competitive substrates for VMAT2.