Photochromic peptidic NPY Y4 receptor ligands

Abstract

The neuropeptide Y (NPY) Y₄ receptor is a G protein coupled receptor, which is targeted by pancreatic polypeptide, a homologue of NPY. Selective Y₄R agonists were suggested as potential therapeutics for the treatment of obesity. Highly potent dimeric peptidic Y₄R agonists, constituting two pentapeptide moieties connected through an aliphatic linker, represent an interesting class of Y₄R ligands. Based on this compound class, photoresponsive Y₄R ligands, containing an azobenzene, azopyrazole, diethienylethene or a fulgimide chromophore were prepared to explore structural requirements of such Y₄R agonists on Y₄R binding. The synthesized Y₄R ligands, containing a non-aliphatic rigid photochromic linker, switch reversibly in aqueous buffer and exhibited high Y₄R affinity throughout. This demonstrated that the replacement of the highly flexible aliphatic linker by a considerably less flexible photochromic linker was well tolerated with respect to Y₄R binding. Differences in Y₄R affinity and activity between the individual photoisomers (varying in spatial orientation and flexibility) were marginal suggesting that the linking element in the dimeric ligands is less critical for the adaptation of high-affinity binding modes at the receptor.