Studies on analgesic oligopeptides. III. Synthesis and analgesic activity after subcutaneous administration of (D-Arg2)dermorphin and its N-terminal tetrapeptide analogs.

[D-Arg2] dermorphin and nineteen N-terminal tetrapeptide analogs were synthesized by a conventional solution method and their analgesic activities after subcutaneous administration to mice were examined. The analgesic effect was assessed by means of the tail pressure test. [D-Arg2] dermorphin was found to have analgesic potency equal to or slightly greater than that of dermorphin. The N-terminal tetrapeptide, H-Tyr-D-Arg-Phe-Gly-OH (I), showed a potency 4.8 times that of morphine and comparable with that of dermorphin on a molar basis. Among the tetrapeptide analogs, several analogs in which Gly4 was replaced by sarcosine or D-Ala exhibited very potent activity more than that of I. On the other hand, replacement of Gly4 by Pro, Leu or D-Leu resulted in a marked decrease in potency. Replacement of either Phe3 by other aromatic amino acid or D-Arg2 by other basic D-amino acid gave analogs with greatly decreased activities. However, one analog whose guanidino functionality on D-Arg2 was blocked by a nitro group, showed activity one-third that of the parent peptide (I). On the basis of these results, the structure-activity relationship for the tetrapeptide is discussed.