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Opioid peptides: synthesis and biological properties of [(N γ -glucosyl,N γ -methoxy)-α,γ-diamino-(S)-butanoyl] 4 -deltorphin-1-neoglycopeptide and related analogues

2003; Royal Society of Chemistry; Volume: 1; Issue: 17 Linguagem: Inglês

10.1039/b306142f

1477-0539

Fernando Filira, Barbara Biondi, Laura Biondi, Elisa Giannini, Marina Gobbo, Lucia Negri, Raniero Rocchi,

Carbohydrate Chemistry and Synthesis

The [D-Ala2]deltorphin I sequence in which the aspartic acid residue is replaced by the Nγ-OCH3-α,γ-diamino (S) butanoyl residue was synthesized using the Fmoc-chemistry-based solid phase procedure. The resulting deltorphin analogue was chemoselectively glucosylated by reaction with unprotected D-glucose (Glc). The Asn4-, (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-β-D-galactopyranosyl)-Asn4- and the (2-acetamido-2-deoxy-D-galactopyranosyl)-Asn4-deltorphin I were also prepared for comparison. The affinity of the new compounds for the δ-opioid receptor was expressed by the inhibition constant (Ki) of the binding of the δ-receptor selective ligand [3H]naltrindole (NTI) to rat brain membrane preparations. The in vitro biological activity of the synthetic peptides was compared with that of the μ-opioid receptor agonist dermorphin in guinea pig ileum (GPI) preparations and with that of the δ-opioid receptor agonist deltorphin I in mouse vas deferens (MVD) preparations. The substitution of Asp4 with Asn failed to affect drastically the Ki and IC50 values for δ-sites, suggesting that an electrostatic interaction does not play an essential role in the binding to δ-opioid sites. The steric hindrance of the side chain of the residue in position 4 affects binding to δ-sites. The increase of the Ki value is smaller when the sugar-peptide linkage involves the γ-nitrogen of the Dab residue in comparison with the Asn amide side chain.