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.
Opioid Peptides. Synthesis and Biological Properties of [(N-gamma-glucosyl, N-gamma-methoxy)-alpha,gamma-diamino(S)butanoyl]4-Deltorphin I Neoglycopeptide and Related Analogues
FILIRA, FERNANDO;BIONDI, LAURA;GOBBO, MARINA;
2003
Abstract
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.
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