To examine the opioid properties of D-MetO2-dermorphin tetrapeptides, eight new analogues based on the following formula, X-Tyr-D-MetO-Phe-aa-Y, were prepared. All these peptides show dose-related naloxone-reversible opioid effects in vitro and in vivo. Substitution of Sar or Gly-ol for Gly4 were well tolerated by the isolated guinea pig-ileum preparation as well as in the tail-flick test, while alkyl-amidation of the C-terminal proved detrimental. The central activity of H-Tyr-D-MetO-Phe-Gly-NH2, the most potent compound in the series, was higher than that of dermorphin. Following intracerebroventricular or subcutaneous administrations in mice, H-Tyr-D-MetO-Phe-Gly-NH2 was about 1500 and 17 times as analgesic as morphine, respectively.