Improving Metabolic Stability by Glycosylation: Bifunctional Peptide Derivatives That Are Opioid Receptor Agonists and Neurokinin 1 Receptor Antagonists

Abstract

In order to obtain a metabolically more stable analgesic peptide derivative, O-β-glycosylated serine (Ser(Glc)) was introduced into TY027 (Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-NH-3’,5’-Bzl(CF3)2) which was a previously reported bifunctional compound with delta/mu opioid agonist and neurokinin-1 receptor antagonist activities, and with a half life of 4.8 h in rat plasma. Incorporation of Ser(Glc) into various positions of TY027 gave analogues with variable bioactivities. Analogue 6 (Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Ser(Glc)-Trp-NH-3’,5’-Bzl(CF3)2) was found to have effective bifunctional activities with a well-defined conformation with two β-turns based on the NMR conformational analysis in the presence of DPC micelles. In addition, 6 showed significant improvement in its metabolic stability (70 ± 9 % of 6 was intact after 24 h incubation in rat plasma). This improved metabolic stability, along with its effective and delta selective bifunctional activities, suggests that 6 could be an interesting research tool and possibly a promising candidate as a novel analgesic drug.

Effect of Peptide Agonists of Peripheral Opioid Receptors on Operant Feeding Behavior and Food Motivation in Rats

“…Some authors reported that the endogenous opioid system plays an important role in the regulation of feeding behavior (including food reinforcement) [8][9][10][11][12]. We proposed and substantiated a hypothesis on reciprocal interaction between the central and peripheral compartments of the endogenous opioid system [4] implying the involvement of the peripheral opioid system in the mechanisms of sensory satisfaction [2,6].…”

Original article Opioid agonist – tachykinin antagonist as a new analgesic with adjuvant anticancer properties

“…The structure and purity of compounds were confirmed by HPLC-MS analysis. The compounds, opi- T Ta ac ch hy yk ki in ni in n h hN NK K1 1 r re ec ce ep pt to or r b bi in nd di in ng g Neurokinin 1 receptor binding assays were performed as previously described [19]. Briefly, recombinant hNK1/CHO cells were grown to 90% confluence in a humidified atmosphere (95% air and 5% CO 2 ) at 37°C, in Ham's F12 medium supplemented with 10% foetal bovine serum, 100 U/mL of penicillin, 100 µg/mL of streptomycin and 500 µg/mL of Geneticin (G 418).…”

P-glycoprotein Trafficking as a Therapeutic Target to Optimize CNS Drug Delivery

“…Such studies are particularly critical for newly developed therapeutics such as opioid analgesic peptides. In fact, many novel opioid peptides have been recently produced and have shown analgesic efficacy (Largent-Milnes et al, 2010; Yamamoto et al, 2009); however, molecular and trafficking mechanisms involved in their CNS delivery have yet to be identified. Discovery of mechanisms that determine brain permeation of these peptides will undoubtedly enable more efficient analgesia and an improved utility of these compounds as potential therapeutics.…”