Cytotoxicity of beta-carbolines in dopamine transporter expressing cells: structure-activity relationships.
Some beta-carbolines (BC) are natural constituents in the human brain deriving from tryptophan, tryptamine, and serotonin. In vitro and animal experiments suggest that BC-cations may cause neurodegeneration with a higher vulnerability of dopaminergic than of other neurons. Despite the possible implication of the BC-cations in the pathogenesis of Parkinson's disease (PD), the underlying mechanisms are poorly understood. The present study further explores the structural requirements for the cytotoxic effects of BCs and searches for additional compounds involved in the pathogenesis of PD. Previous studies were now extended to serotonin-derived BCs, tetrahydro-BCs, a BC-dimer, and a BC-enantiomer to reveal possible stereoselectivity. 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.
Wernicke
Catrin
C
Charité-University Medicine, Department of Psychiatry, CBF, Section Clinical Neurobiology, Eschenallee 3, 14050 Berlin, Germany. catrin.wernicke@charite.de
Schott
Yvonne
Y
Enzensperger
Christoph
C
Schulze
Gert
G
Lehmann
Jochen
J
Rommelspacher
Hans
H
D002243:Carbolines / Q000737:chemistry* / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation; D006801:Humans; D015394:Molecular Structure; D012701:Serotonin / Q000031:analogs & derivatives / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014363:Tryptamines / Q000494:pharmacology
D002243:Carbolines; D050483:Dopamine Plasma Membrane Transport Proteins; D014363:Tryptamines; D012701:Serotonin