Potent μ-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[d-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation

To optimize the structure of a μ-opioid receptor ligand, analogs H-Tyr-c[d-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity was tested. The analog containing a Phe3 was identified as not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at d-Lys2-Xxx3 is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity toward the μ-opioid receptor.