Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2, EM-2) is a putative endogenous μ-opioid receptor ligand. To study the structure–activity relationship against its receptor, we introduced N–O turns into EM-2 and got the analogues with potent affinities for μ-opioid receptor. Our results indicated that N–O turn structures at the Pro2-aminoxy-Phe3 position of EM-2 analogues played important roles for their affinities. These novel analogues with N– ...