Project 13: Characterization of the molecular mode of action of novel psychoactive substances

Between 50 and 100 Novel Psychoactive Substances (NPS) appear each year on the illicit drug market. Neurotransmitters transporters are located in presynaptic specializations. They inactivate neurotransmitter-mediated neurotransmission following exocytotic release by a simple reuptake mechanism. Recent crystallographic examination of mammalian neurotransmitter transporters provide a structural scaffold which supports transport by an alternative access mechanism. Monoamine transporters are a target of clinically relevant drugs: (i) antidepressants competitively block the reuptake of monoamines. Thereby, these compounds enhance the extracellular monoamine concentration which is relevant for clinical success. (ii) amphetamines and cathinones, which behave as substrates of the transporters, trigger non-exocytotic neurotransmitter release (efflux). The exact molecular mechanism of the psychostimulant action, however, still remains enigmatic. Novel psychoactive substances comprise psychostimulants, primarily the chemical substances classes of amphetamines and cathinones.

They are untested illicit compounds that carry perils, but also hold promises as future medication. Before moving from a possibly dangerous and toxic compound to a druggable lead, thorough characterization of its mode of action is essential. In parallel, ex- ploitation of in house available compound series of amphetamine and cathinone with specifically designed substitutes allows for enlight- ening structural and functional properties of DAT. The combination of the two aims will allow for gathering useful information for policy makers and indicate a potential for exploitation in the long-term future. In addition, our amphetamine and cathinone tool compounds will further elucidate the subtle differences between transported substrates and non-transported inhibitors. The objectives of ESR13 are: (i) to elucidate the mechanism of action of psychostimulant NPS by application of biochemical tracer flux assays, binding assays and elec- trophysiological approaches. (ii) to test already available amphetamine and cathinone compound series to identify changes in biochemical transport parameters. (iii) to specify the properties that discriminate substrates from an inhibitor.