The analgesic activity of D-Arg2-dermorphin and its N-terminal tetrapeptide analogs after subcutaneous administration...

D-Arg2-dermorphin and its nineteen N-terminal tetrapeptide analogs were prepared, and their analgesic activities after subcutaneous administration in mice and the stability of a D-Arg2-dermorphin tetrapeptide to enzymatic degradation were examined. The analgesic effect was assessed by the tail pressure test. D-Arg2-dermorphin was found to have analgesic potency equal to or slightly greater than that of dermorphin. In a series of tetrapeptide analogs, a very pronounced activity greater than that of morphine was observed for analogs of the following structure, H-Tyr-D-Arg-Phe-X-OH (X = Gly, sarcosine and D-Ala) or its esters. Replacement of D-Arg2 by D-Arg(NO2), D-homoarginine or D-Lys resulted in a decrease in potency, suggesting that the guanidino group and side chain length of D-Arg2 are of great importance for a higher activity. D-Arg2-tetrapeptide (H-Tyr-D-Arg-Phe-Gly-OH) was found to be more stable than the parent tetrapeptide (H-Tyr-D-Ala-Phe-Gly-OH) to cleavage both by aminopeptidase M and by carboxypeptidase Y.