Opioid peptides: synthesis and biological properties of [(Ny-glucosil,Ny-methoxy)-a,y-diamino-(S)-butanoyl]4-deltorphin-I-neoglycopeptide and related analogues.

The [D-Ala(2)] deltorphin I sequence in which the aspartic acid residue is replaced by the N-gamma-OCH3-alpha,gamma-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 Asn(4)-, (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-D-galactopyranosyl)-Asn(4)- and the (2-acetamido-2-deoxy-D-galactopyranosyl)-Asn(4)-deltorphin I were also prepared for comparison. The affinity of the new compounds for the delta-opioid receptor was expressed by the inhibition constant (K-i) of the binding of the delta-receptor selective ligand [H-3]naltrindole (NTI) to rat brain membrane preparations. The in vitro biological activity of the synthetic peptides was compared with that of the mu-opioid receptor agonist dermorphin in guinea pig ileum (GPI) preparations and with that of the delta-opioid receptor agonist deltorphin I in mouse vas deferens (MVD) preparations. The substitution of Asp(4) with Asn failed to affect drastically the K-i and IC50 values for delta-sites, suggesting that an electrostatic interaction does not play an essential role in the binding to delta-opioid sites. The steric hindrance of the side chain of the residue in position 4 affects binding to delta-sites. The increase of the K-i value is smaller when the sugar-peptide linkage involves the gamma-nitrogen of the Dab residue in comparison with the Asn amide side chain.