Structure‐activity relationships of met 5 ‐ and leu s ‐enkephalin analogues

Summary 1. The effect of various analogues of met 5 ‐ and leu 5 ‐enkephalin were determined on the reduction in twitch height of the electrically‐stimulated longitudinal muscle preparation of the guinea‐pig ileum and of the isolated mouse vas deferens. 2. In the guinea‐pig ileum, D‐alanine 2 ‐met 5 ‐enkephalin was the most potent whereas leu 5 ‐enkephalin was the most potent in the mouse vas deferens. 3. The met 5 ‐enkephalin analogues were more effective in reducing the twitch height of the ileum than they were in depressing that of the vas deferens preparation. The leu 5 ‐enkephalin analogues were more potent in their effects on the mouse vas deferens than they were on the guinea‐pig ileum. 4. When a peptide bond is replaced by a glycol bond as in glycol 2‐3 ‐leu 5 ‐enkephalin there is a marked reduction in opiate‐like activity. 5. Substitution of a D‐alanine residue for the glycine 2 residue, as in D‐alanine 2 ‐met 5 ‐enkephalin, increases the duration and potency of opiate‐like activity. 6. These results confirm that modification of either met 5 ‐ or leu 5 ‐enkephalin can alter the opiate‐like potency of the resulting analogues. It appears that an intact tyrosyl residue of leu 5 ‐enkephalin is essential for such activity and that substitution of a D‐alanine 2 residue for the glycine 2 residue confers resistance to enzymatic degradation on the met 5 ‐enkephalin peptide. In addition, the glycine 2‐3 peptide bond is essential for opiate‐like activity.