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

This article describes new deltorphin I analogs in which phenylalanine residues were replaced by the corresponding (R) or (S)-alpha-benzyl-beta-azidoalanine, alpha-benzyl-beta-(1-pyrrolidinyl)alanine, alpha-benzyl-beta-(1-piperidinyl)alanine, and alpha-benzyl-beta-(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 [H-3]DAMGO (a mu ligand) and [H-3]DELT (a delta ligand). The affinity of analogs containing (R) or (S)-alpha-benzyl-beta-azidoalanine in position 3 to delta-receptors strongly depended on the chirality of the alpha,alpha-disubstituted residue. The conformational behavior of peptides modified with (R) or (S)-alpha-benzyl-beta-(1-piperidinyl)Ala, which displays the opposite selectivity, was analyzed by H-1 and C-13 NMR. The mu-selective Tyr-D-Ala-(R)-alpha-benzyl-alpha-(1-piperidinyl)Ala-Asp-Val-Val-Gly-NH2 lacks the helical conformation observed in the delta-selective TyrD- Ala-(S)-alpha-benzyl-beta-(1-piperidinyl) Ala-Asp-Val-Val-Gly-NH2. Our results support the proposal that differences between delta- and mu-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.