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 )‐ α ‐benzyl‐ β ‐azidoalanine, α ‐benzyl‐ β ‐(1‐pyrrolidinyl)alanine, α ‐benzyl‐ β ‐(1‐piperidinyl)alanine, and α ‐benzyl‐ β ‐(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 [ 3 H]DAMGO (a μ ligand) and [ 3 H]DELT (a δ ligand). The affinity of analogs containing ( R ) or ( S )‐ α ‐benzyl‐ β ‐azidoalanine in position 3 to δ ‐receptors strongly depended on the chirality of the α , α ‐disubstituted residue. The conformational behavior of peptides modified with ( R ) or ( S )‐ α ‐benzyl‐ β ‐(1‐piperidinyl)Ala, which displays the opposite selectivity, was analyzed by 1 H and 13 C NMR. The μ ‐selective Tyr‐ d ‐Ala‐( R )‐ α ‐benzyl‐ β ‐(1‐piperidinyl)Ala‐Asp‐Val‐Val‐Gly‐NH 2 lacks the helical conformation observed in the δ ‐selective Tyr‐ d ‐Ala‐( S )‐ α ‐benzyl‐ β ‐(1‐piperidinyl)Ala‐Asp‐Val‐Val‐Gly‐NH 2 . Our results support the proposal that differences between δ ‐ and μ ‐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.