Synthetic studies on enkephalin analogs. I. Potent analgesic activity of H-Tyr-D-Ala-Gly-Phe-NHNH-CO-R (R=lower alkyl).

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Abstract
Tetrapeptide hydrazide analogs [30] of enkephalin, H-Tyr-D-Ala-Gly-Phe-NHN-(R1)-R2 (R1, R2 = H, alkyl or acyl), were synthesized. The analgesic activities of these peptides were tested in mice after i.v. or s.c. injection, and compared with that of morphine. Among the analogs synthesized, the tetrapeptide acyl-hydrazide analog, H-Tyr-D-Ala-Gly-Phe-NHNH-CO-R (R = lower alkyl), was the most active and showed analgesic activity 10 times more potent than that of the tetrapeptide amide analog, H-Tyr-D-Ala-Gly-Phe-NH2, and half as potent as that of morphine. Structure-activity relations in the hydrazide part of enkephalin analogs of this new type are discussed.