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

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

The impact of β-azido(or 1-piperidinyl) methylamino acids in position 2 or 3 on biological activity and conformation of dermorphin analogues

The synthesis of new dermorphin analogues is described. The (R)-alanine or phenylalanine residues of natural dermorphin were substituted by the corresponding α-methyl-β-azidoalanine or α-benzyl-β-azido(1-piperidinyl)alanine residues. The potency and selectivity of the newanalogueswere evaluated by a competitive receptor binding assay in rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). The most active analogue in this series, Tyr-(R)-Ala-(R)-α-benzyl-β-azidoAla-Gly-Tyr-Pro-Ser-NH2 and its epimer were analysed by 1H and 13C NMR spectroscopy and restrainedmolecular dynamics simulations. The dominant conformation of the investigated peptides depended on the absolute configuration around Cα in the α-benzyl-β-azidoAla residue in position 3. The (R) configuration led to the formation of a type I β-turn, whilst switching to the (S) configuration gave rise to an inverse β- turn of type I′, followed by the formation of a very short β-sheet. The selectivity of Tyr-(R)-Ala-(R) and (S)-α-benzyl-β-azidoAla-Gly- Tyr-Pro-Ser-NH2 was shown to be very similar; nevertheless, the two analogues exhibited different conformational preferences