SYNTHESIS OF 2 ENZYME RESISTANT ENKEPHALIN ANALOGS POSSESSING ENHANCED ANALGESIC ACTIVITY

  • 1 January 1978
    • journal article
    • research article
    • Vol. 20  (1) , 59-68
Abstract
Two enzyme resistant analogs of methionine enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) were synthesized and tested for morphine-like properties in the stimulated guinea pig ileum, rat tail-flick, mouse tail-flick and for stability in whole brain homogenates. The 2 analogs are: N.alpha.-methyl-tyrosyl-glycyl-glycyl-phenylalanyl-des-carboxy-norleucine and tyrosyl-D-alanyl-glycyl-phenylalanyl-des-carboxy-norleucine. Both peptides were completely stable for 90 min when incubated with whole brain homogenate (rat) while methionine enkephalin was rapidly destroyed (t1/2 [half-life] = 4 min at 37.degree. C). In addition, each was more potent than methionine enkephalin in the stimulated guinea pig ileum assay and had good activity in the tail-flick test when given intraventricularly in mice or via indwelling catheters into the periaqueductal gray of rats. Each of these activities was blocked by naloxone. The antinociceptive activity of these peptides was much reduced in morphine tolerant animals.