Small potent ligands to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor.

Angiotensin IV analogues encompassing aromatic scaffolds replacing parts of the back bone of angiotensin IV have been synthesized and evaluated in biological assays. Several of the ligands displayed high affinities to the insulin-regulated aminopeptidase (IRAP)/AT4 receptor. Displacement of the C-terminal of angiotensin IV with an ortho substituted aryl acetic acid derivative delivered the ligand (4) that exhibited the highest binding affinity (Ki =1.9 nM). The high affinity of this ligand provides strong support for the hypothesis that angiotensin IV adopts a u-turn in the C-terminal of its bioactive conformation.
Ligand 4 inhibits both human IRAP and aminopeptidase N activity and induces at low concentrations proliferation of adult neuronal stem cells. Furthermore, ligand 4 is degradated considerably more slowly in membrane preparations than angiotensin IV. Hence, it might constitute a suitable research tool for biological studies on the (IRAP)/AT4 receptor.