Synthesis and analgesic properties of two leucine-enkephalin analogues containing a conformationally restrained N-terminal tyrosine residue.

Two analogues of Leu-enkephalin, in which the terminal tyrosine-1 residue has been replaced by a conformationally restrained tyrosine analogue, have been synthesized by classical solution methods, and their opiate agonist potencies on electrically stimulated guinea pig ileum and mouse vas deferens preparations were determined in comparison with Leu-enkephalin. The restriction in the degree of freedom of the tyrosine moiety in [(2-amino-6-hydroxy-2-tetralinyl)carbonyl]glycylglycylphenylalanylleucine methyl ester (3e) leads to a 7 to 8 times higher agonist activity at the mu-receptor subtype in guinea pig ileum when compared to Leu-enkephalin, and an almost 30-fold decrease in potency, vs. Leu-enkephalin, on mouse vas deferens preparation. [(2-Amino-5-hydroxy-2-indanyl)carbonyl]-glycylglycylphenylalanylleucine methyl ester (2e) was inactive in the above tests. These results demonstrate the differential effect of restricting conformational flexibility on receptor recognition. Neither analogue had any analgesic properties when evaluated by the hot-plate test in mice after sc and icv administration.