Synthetic Studies on Enkephalin Analogs. III. A Highly Potent Enkephalin Analog, H-Tyr-D-Met (O)-Gly-Phe-NHNH-CO-CH₂CH₃

Abstract

Thirty-five tetrapeptide acyl-hydrazide analogs of enkephalin substituted at position 2 were synthesized. Substitution of D-Ala at position 2 of H-Tyr-D-Ala-Gly-Phe-NHNH-CO-R (R=lower alkyl), by D-Met (O), D-Gln, D-Glu (NH-CH₃) or D-Thr enhanced the analgesic potency, but substitution by D-Glu or Ser resulted in an analog with no antinociceptive activity. Among the analogs synthesized, the D-Met (O)-analog was the most potent and H-Tyr-D-Met (O)-Gly-Phe-NHNH-CO-CH₂CH₃ exhibited analgesic activtiy four times more potent than that of morphine in mice following subcutaneous injection. Structure-activity relations for position 2 of the enkephalin-like tetrapeptide are discussed.