Tyrosine-modified analogs of methionine-enkephalin and their effects on the mouse vas deferens

Eighteen analogs of Met-enkephalin were synthesized in order to examine features of the N-terminal tyrosine (Tyr) residue responsible for activity on the mouse vas deferens. The most critical part of the tyrosine side-chain was its phenolic hydroxyl group which, in terms of biological activity, was highly sensitive to small changes and to the inclusion of fluorine or methyl groups in the aromatic ring. In contrast, the free amino group was not as sensitive to alterations. Single amino acid extensions had only modest effects on activity; however, beta and D-amino acid extensions virtually destroyed activity. Although the Tyr residue might be considered a promising part of the opiate peptides for the development of competitive antagonists, none of our inactive analogs were able to antagonize enkephalin and were, therefore, without binding affinity towards opiate receptors in the vas deferens.