Structure-activity relationships of enkephalins in the stimulated guinea pig ileum

A number of analogs and homologs of methionine-enkephalin (H.Tyr. Gly.Gly.Phe.Met.OH) have been synthesized by the Merrifield method of solid phase peptide synthesis. Each peptide was assayed by inhibition of electrically evoked contraction of the guinea pig ileum. The minimum sequence required for biological activity in this preparation was found to be the pentapeptide unit. Methionine was readily replaced by norleucine to give an analog with approximately 50% of the potency of the parent compound. Leucineenkephalin has about 15-20% of the potency of the methionine dervative. 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 receptor site is discussed.