Studies on analgesic oligopeptides. VI. Further studies of synthesis and biological properties of tripeptide alkylamides, Tyr-D-Arg-Phe-X.

Abstract

Nine analogs based on a structure of Tyr-D-Arg-Phe-X (X = alkylamides or alkylhydrazide containing electron-withdrawing atoms or groups) were newly synthesized and their biological properties were examined by the opioid receptor binding properties of mu-, delta- and kappa-receptors, guinea-pig ileum (GPI) assay and analgesic activity in the tail pinch test after subcutaneous administration in mice. Analogs with X = NHCF2CF3, Sar-ol, or NH(CH2)2CN showed potent activities in the GPI and analgesic assays and high affinity for mu-receptor. An analog with X = taurinamide was found to possess 4-fold higher mu-receptor selectivity than that of [D-Ala2, MePhe4, Gly-ol5]enkephalin (DAGO). The receptor binding properties of previously reported analogs [Chem. Pharm. Bull., 33, 1528 (1985); ibid., 33, 4865 (1985); ibid., 36, 4834 (1988)] were also examined for overall discussion of the structure-activity relationships of this series of tripeptide amides.