Selective ligands for Y1 receptors are of interest as anti-cancer drug carriers. Truncated peptide sequences of a natural ligand, Neuropeptide Y, will be prepared in which two key residues Thr-32 and Gln-34 will be replaced by conformationally restricted cyclobutane -amino acids. These components have several advantages over cyclopropane-derived derivatives, which are currently the most promising materials. A library of the designated cyclobutane -amino acids will be made available using a general photochemical synthetic strategy, which will allow full evaluation of the consequences of stereochemistry and side chain functions for the potency and selectivity of receptor binding. Comparison with NPY analogs which incorporate other cyclic -amino acid substitutions will also be made. The best ligand will be tested for its ability to target deliver a cytotoxic natural product to Y1 receptor-rich cells.
