Syntheses of potent Leu-enkephalin analogs possessing β-hydroxy-α,α-disubstituted-α-amino acid and their characterization to opioid receptors

Novel Leu-enkephalin (Leu-Enk) (1) analogs possessing various types of α-substituted serine instead of its glycine residue in the position 2 were synthesized via an efficient O,N-migration method. The binding characteristics of the synthetic analogs using Chinese hamster ovary (CHO) cells expressed cloned rat μ-, δ-, and κ-receptors revealed that [(1R,2S)-Ahh2]Enk (7) was the most potent agonist of δ-opioid receptors among all the synthetic analogs tested, and was 10 times more potent than the native Leu-Enk.