Synthesis of two enzyme resistant enkephalin analogs possessing enhanced analgesic activity.
Two enzyme resistant analogs of methionine enkephalin (H-Try-Gly-Gly-Phe-Met-OH) have been 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 two analogs are: Nalpha-Methyl-Tyrosyl-Glycyl-Glycyl-Phenylalanyl-des-carboxy-Norleucine (I) and Tyrosyl-D-Alanyl-Glycyl-Phenylalanyl-des-carboxy-Norleucine (II). Both peptides were completely stable for 90 minutes when incubated with whole brain homogenate (rat) while methionine enkephalin was rapidly destroyed (t1/2=4 min at 37 degrees 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 were blocked by naloxone. Interestingly, the antin-ociceptive activity of these peptides was much reduced in morphine tolerant animals.
D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D004361:Drug Tolerance; D004723:Endorphins / Q000138:chemical synthesis*; D004745:Enkephalins / Q000037:antagonists & inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors
D000700:Analgesics; D004723:Endorphins; D004745:Enkephalins; D009270:Naloxone; D009020:Morphine