Synthesis, Biological Activity, and NMR-Based Structural Studies of Deltorphin I Analogs Modified in Message Domain with a New a,a-Disubstituted Glycines

Abstract

This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)-a-benzyl-b-azidoalanine, a-benzyl-b- (1-pyrrolidinyl)alanine, a-benzyl-b-(1-piperidinyl)alanine, and a-benzyl-b-(4-morpholinyl)-alanine residues. The potency and selectivity of the new analogs were evaluated by a competitive receptor binding assay in the rat brain using [3H]DAMGO (a l ligand) and [3H]DELT (a d ligand). The affinity of analogs containing (R) or (S)-abenzyl- b-azidoalanine in position 3 to d-receptors strongly depended on the chirality of the a,a-disubstituted residue. The conformational behavior of peptides modified with (R) or (S)-a-benzyl-b-(1-piperidinyl)Ala, which displays the opposite selectivity, was analyzed by 1H and 13C NMR. The l-selective Tyr-D-Ala-(R)- a-benzyl-b-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 lacks the helical conformation observed in the d-selective Tyr- D-Ala-(S)-a-benzyl-b-(1-piperidinyl)Ala-Asp-Val-Val-Gly- NH2. Our results support the proposal that differences between d- and l-selective opioid peptides are attributable to the presence or absence of a spatial overlap between the N-terminal message domain and the C-terminal address domain.