Synthesis and evaluation of new endomorphin-2 analogues containing (Z)-α,β-didehydrophenylalanine (δZPhe) residues

New endomorphin-2 (EM-2) analogues incorporating (Z)-α,β- didehydrophenylalanine (δZPhe) in place of the native phenylalanine in EM-2 are reported. Tyr-Pro-δZPhe-Phe-NH 2 {[δZPhe3]EM-2} (1), Tyr-Pro-Phe-δZPhe-NH2 {[δZPhe 4]EM-2} (2), and Tyr-Pro-δZPhe- δZPhe-NH2 {[δZPhe 3,4]EM-2}(3) have been synthesized, their opioid receptor binding affinities and tissue bioassay activities were determined, and their conformational properties were examined. Compound 2 shows high μ opioid receptor selectivity and μ agonist activity comparable to those of the native peptide. The conformation adopted in solution and in the crystal by N-Boc-Tyr-Pro-δZPhe-Phe-NH2 (8) is reported. © 2010 American Chemical Society.