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

Abstract

The [D-Ala2]deltorphin 1 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 Asn4-, (2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-beta-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 delta-opioid receptor was expressed by the inhibition constant (Ki) of the binding of the delta-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 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 Asp4 with Asn failed to affect drastically the Ki 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 Ki value is smaller when the sugar-peptide linkage involves the gamma-nitrogen of the Dab residue in comparison with the Asn amide side chain.

Lanthanide(III) Complexes with Two Hexapeptides Incorporating Unnatural Chelating Amino Acids: Secondary Structure and Stability

“…The three-step synthetic pathway to 2 starting from commercially available l-homoserine (l-Hse) was reported by Rocchi and co-workers. [23] However, in the second step, Fmoc-Hse-OBn was isolated in only 48 % yield probably because of the prompt lactonization of this intermediate. The synthesis of Fmoc-Hse-OBn was improved by conducting the benzylation in anhydrous DMSO using the conditions reported for the synthesis of Fmoc-SerOBn.…”

“…1 H NMR and ES-MS analysis data for the crude solid were compatible with published data for the purified product [23] except for the presence of trace amounts of DMSO. The solid was subjected without further purification to Swern oxidation following the procedure reported by Rocchi et al [23] Aldehyde 2 (1.782 g) was obtained after SiO 2 column chromatography (eluent: cyclohexane/EtOAc, 2:1, v/v).…”

“…Aldehyde 2: Compound 1 [23] (3.128 g, 9.16 mmol), KHCO 3 (1.377 g, 13.76 mmol, 1.5 equiv) and tetrabutylammonium iodide (0.3385 g, 0.916 mmol, 0.1 equiv) were dissolved in dry DMSO (18 mL) under argon. The resulting white suspension was stirred at room temperature for 10 min to obtain a clear solution.…”

“…The solid was subjected without further purification to Swern oxidation following the procedure reported by Rocchi et al [23] Aldehyde 2 (1.782 g) was obtained after SiO 2 column chromatography (eluent: cyclohexane/EtOAc, 2:1, v/v). Yield: 45 % over two steps (lit.…”

Synthesis and Application of Glycopeptide and Glycoprotein Mimetics

“…Glycosylation with the sterically hindered threonine derivate 104, however, failed. The same strategy was successfully applied by Rocchi et al for the synthesis of opioid deltorphin I analogues [153].…”