Synthesis and opioid activity of partial retro-inverso analogs of dermorphin

We studied the effect of partial retro-inverso modification of selected peptide bonds of dermorphin (H-Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-NH2. The modifications concern two consecutive peptide bonds (Phe3-Cly4-Tyr5, I) or a single one (Gly4-Tyr5-, II or Phe3-Gly4, III). All pseudoheptapeptides showed low opioid activity in the in vitro and in vivo tests. Compound III has a biological potency comparable to that of morphine but only 2-5% of original dermorphin when tested in guinea pig ileum preparation and in mice tail-flick assay after intracerebro or subcutaneous administration.