Cytotoxicity of β-carbolines in dopamine transporter expressing cells: Structure-activity relationships

Neutral, rather lipophilic BCs may pass the plasma membrane and the outer and inner mitochondrial membranes by diffusion whereas the cationic, more polar compounds, can be transported by the dopamine transporter (DAT). In the present study, 4 out of 17 BC-cations caused DAT-independent toxicity. This number is unexpected in view of previous findings that all BC-cations are transported by DAT. 3-Carboxylated and 6-methoxylated BCs were poor substrates. The size alone does not seem to be a limiting factor. A dimeric BC-cation was readily transported by the DAT despite its much larger structure compared to dopamine. Furthermore, (R)-enantiomers were preferentially transported. The neutral BCs were approximately one order of magnitude less toxic than the cationic BCs. There are considerable differences of the transport efficiency between the BCs. Potent cytotoxic tetrahydro-BCs were detected. Because precursor tetrahydro-BCs are present in the brain, the search for the occurrence of these compounds in human brain is warranted.