N-acyl Dopamines - renoprotective therapeutics, acting on TRPV1 signaling

NOD is a synthetic N - acyl dopamine which exhibits anti - inflammatory, reno - protective and cytoprotective properties. NOD has become an interesting drug candidate for clinical use in the setting of ischemia - induced acute kidney injury and Transplantation. This thesis investigates the relevant chemical and biological properties that grant NOD reno - protective effects in these contexts. The experimental studies described in this thesis demonstrate firstly, that NOD conveys protection in the setting of ischemia induced AKI via TRPV1 activation. Secondly, different molecular entities within NOD are required for TRPV1 activation and for its anti - inflammatory property. Thirdly, in vivo tissue distribution and elimination kinetics of NOD using [18F]F – labelled NOD demonstrate a rapid renal and hepatobiliary clearance. Finally, NOD’s prominent redox active nature significantly affects the cell behaviour, i.e. NOD induces ER stress resulting in the induction of the unfolded protein response. This thesis provided insight in the biodistribution of NOD and pins down its renoprotective effect in vivo to TRPV1 activation. Although being a promising drug candidate for the treatment of acute kidney injury, detailed pharmacodynamic and pharmacokinetic studies are warranted before clinical implementation of NOD.

Dissertation: http://hdl.handle.net/11370/ba0d40df-653a-40ee-97b9-cff26b5a86bd