Studies on analgesic oligopeptides. V. Structure-activity relationship of tripeptide alkylamides, Tyr-D-Arg-Phe-X.

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Abstract
Twenty-one analogs based on the structure Tyr-D-Arg-Phe-X (X = OH, alkyl ester, alkyl-amide or amino acid having a different carbon chain) were synthesized by the solution method and their analgesic activities were tested after subcutaneous (s. c.) administration in mice. Most tripeptide alkylamides showed no analgesia at a dose of 10 mg/kg, s. c. However, some tripeptide alkylamides having the hydroxyl group on the alkyl moiety showed greater activity than morphine. Introduction of the carboxyl group on the alkyl moiety also led to tetrapeptide analogs with potent analgesia, e.g., the compound with X = .beta.-alanine is 33 times more potent than morphine on a molar basis. These results suggest that proper carbon chain lengths and the presence of an oxygen atom at the fourth position are important for high analgesic activity in the series of D-Arg2-dermorphin analogs.

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