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 new analogues were evaluated by a competitive receptor binding assay in rat brain using [(3) H]DAMGO (a μ ligand) and [(3) H]DELT (a δ ligand).

Synthesis, binding affinities and metabolic stability of dimeric dermorphin analogs modified with β3-homo-amino acids.

In this study, proteinogenic amino acids residues of dimeric dermorphin pentapeptides were replaced by the corresponding β(3)-homo-amino acids. The potency and selectivity of hybrid α/β dimeric dermorphin pentapeptides were evaluated by competetive receptor binding assay in the rat brain using [3H]DAMGO (a μ ligand) and [3H]DELT (a δ ligand). Tha analog containing β(3)-homo-Tyr in place of Tyr (Tyr-D-Ala-Phe-Gly-β(3)-homo-Tyr-NH-)2 showed good μ receptor affinity and selectivity (IC50 = 0.

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.

Biphalin analogs containing β(3)-homo-amino acids at the 4,4' positions: Synthesis and opioid activity profiles.

Biphalin, a synthetic opioid octapeptide with a palindromic sequence has high analgesic activity. Biphalin displays a strong affinity for μ and δ-opioid receptors, and a significant to κ-receptor. The paper reports the synthesis of novel analogs of biphalin containing β(3)-homo-amino acid residues at the 4,4' positions and a hydrazine or 1,2-phenylenediamine linker.

Analogues of deltorphin I containing conformationally restricted amino acids in position 2: structure and opioid activity.

New analogues of deltorphin I (DT I, Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2 ), with the D-Ala residue in position 2 replaced by α-methyl-β-azido(amino, 1-pyrrolidinyl, 1-piperidinyl or 4-morpholinyl)alanine, were synthesized by a combination of solid-phase and solution methods. All ten new analogues were tested for receptor affinity and selectivity to μ- and δ-opioid receptors. The affinity of analogues containing (R) or (S)-α-methyl-β-azidoalanine in position 2 to δ-receptors strongly depended on the chirality of the α,α-disubstituted residue.

The biological consequences of replacing D-Ala in biphalin with amphiphilic α-alkylserines.

Biphalin, a synthetic opioid peptide with a broad affinity for all opioid receptors (δ, μ, and κ) and high antinociceptive activity, has been under extensive study as a potential analgesic drug. This study presents the synthesis and biological properties of four new analogues of biphalin containing amphiphilic α-alkylserines in position 2 and 2'. The incorporation of bulky α,α-disubstituted amino acids in the peptide chain using standard peptide chemistry is often unsuccessful.