The norepinephrine transporter as a target for natural products and derivatives

The Norepinephrine (=noradrenaline) transporter (NET) belongs besides serotonin and dopamine transporters to the family of monoamine transporters, regulating the re-uptake of norepinephrine released from neurons [1]. Several drugs binding to the norepinephrine transporter have been utilized therapeutically for the treatment of various disorders of the central (CNS) and peripheral nervous system (PNS), or cardiovascular disorders. In particular, norepinephrine re-uptake inhibitors are useful drugs in the therapy of depression, attention deficit disorder, obsessive compulsive disorder and panic disorder. Natural products as lead substances in the synthesis of bioactive therapeutics are an emerging field. In order to assess the inhibitory potential of natural products on the norepinephrine transporter, we have recently established a new screening assay based on COS-7 cells, transiently transfected with human norepinephrine transporter cDNA. Norepinephrine uptake studies were carried out using tritium labelled norepinephrine by quantifying radioactivity via liquid scintillation counting. The known selective inhibitor nisoxetine and the tricyclic antidepressant desipramine were used as positive controls with IC 50 values comparable to literature data [2]. Heterocyclic and biphenyltype skeletons with different kinds of saturated and unsaturated, generally unbranched alkyl side chains showed moderate activity. These natural products as well as a set of derivatives thereof were investigated at different screening concentrations ranging from 10 to 100µM. Promising candidates are currently under further investigation. References: [1] Mandela, P., Ordway, G. A. (2006)J. Neurochem. 97:310–333. [2] Olivier, B. et al. (2000) Prog. Drug Res. 54:59–119.