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

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Abstract
[D-Arg2]dermorphin and 19 N-terminal tetrapeptide analogs were synthesized by a conventional solution method and their analgesic activities after s.c. administration to mice were examined. The analgesic effect was assessed by means of the tail pressure test. [D-Arg2]dermorphin had 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. 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. One analog whose guanidino functionality on D-Arg2 was blocked by a nitro group, showed activity 1/3 that of the parent peptide (I). The structure-activity relationship for the tetrapeptide is discussed.