STRUCTURE-ACTIVITY-RELATIONSHIPS OF ENKEPHALINS IN STIMULATED GUINEA-PIG ILEUM

Abstract

A number of analogs and homologs of methionine-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) were synthesized by the Merrifield method of solid phase peptide synthesis. The inhibition of electrically evoked contraction of the guinea pig ileum was used as a screening assay because of the similarity of the potency of morphine and other narcotic analgesics in this model compared to their potency as analgesics in animals and man. The minimum sequence required for biological activity in this preparation was the pentapeptide unit. Methionine was readily replaced by norleucine to give an analog with approximately 50% of the potency of the parent compound. Leucine-enkephalin had about 15-20% of the potency of the methionine derivative. Modification of the N-terminal tyrosine moiety (i.e., substitution by phenylalanine or removal of the amino group) practically abolished activity. Incorporation of O-methyl tyrosine into the peptide reduced potency to 1% of the parent compound. The significance of these and other findings in terms of the topography of the guinea pig ileum opiate receptor site was discussed.