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

Abstract

The [D-Ala²]deltorphin I sequence in which the aspartic acid residue is replaced by the N^γ-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 (K_i) 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 K_i 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 K_i value is smaller when the sugar-peptide linkage involves the γ-nitrogen of the Dab residue in comparison with the Asn amide side chain.