The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia

Abstract

In previous work we evaluated an opioid glycopeptide with mixed μ/δ-opioid receptor agonism that was a congener of leu-enkephalin, MMP-2200. The glycopeptide analogue showed penetration of the blood–brain barrier (BBB) after systemic administration to rats, as well as profound central effects in models of Parkinson’s disease (PD) and levodopa (L-DOPA)-induced dyskinesia (LID). In the present study, we tested the glycopeptide BBI-11008 with selective δ-opioid receptor agonism, an analogue of deltorphin, a peptide secreted from the skin of frogs (genus Phyllomedusa). We tested BBI-11008 for BBB-penetration after intraperitoneal (i.p.) injection and evaluated effects in LID rats. BBI-11008 (10 mg/kg) demonstrated good CNS-penetrance as shown by microdialysis and mass spectrometric analysis, with peak concentration levels of 150 pM in the striatum. While BBI-11008 at both 10 and 20 mg/kg produced no effect on levodopa-induced limb, axial and oral (LAO) abnormal involuntary movements (AIMs), it reduced the levodopa-induced locomotor AIMs by 50% after systemic injection. The N-methyl-D-aspartate receptor antagonist MK-801 reduced levodopa-induced LAO AIMs, but worsened PD symptoms in this model. Co-administration of MMP-2200 had been shown prior to block the MK-801-induced pro-Parkinsonian activity. Interestingly, BBI-11008 was not able to block the pro-Parkinsonian effect of MK-801 in the LID model, further indicating that a balance of mu- and delta-opioid agonism is required for this modulation. In summary, this study illustrates another example of meaningful BBB-penetration of a glycopeptide analogue of a peptide to achieve a central behavioral effect, providing additional evidence for the glycosylation technique as a method to harness therapeutic potential of peptides.

Ischemic preconditioning protects the heart against ischemia-reperfusion injury in chronic kidney disease in both males and females

“…After the end of reperfusion, in a subgroup of hearts, atria were removed, and the total ventricles were used to determine the infarcted area as described previously [ 34 , 35 ]. Briefly, frozen ventricles were cut to 7–8 equal slices and placed into triphenyl-tetrazolium chloride solution (Sigma-Aldrich, Saint Louis, MO, USA) for 10 min at 37 °C followed by a 10 min formaldehyde fixation and phosphate buffer washing steps.…”

Food-Derived Peptides: Beneficial CNS Effects and Cross-BBB Transmission Strategies

“…After glycosylation, the permeability, half-life, and analgesic activity of the BBB significantly improves . O-Linked glycosylation of the opioid peptide amide (Tyr- d -Thr-Gly-Phe-Leu-Ser-NH2) on Ser6 significantly increases BBB permeability (from 1.0 ± 0.2 μL min –1 ·g –1 to 2.2 ± 0.2 μL min –1 ·g –1 ), and enhances serum stability and the pain effect . Further study has found that different sugar-modified peptides lead to different tissue distributions.…”

“…200 O-Linked glycosylation of the opioid peptide amide (Tyr-D-Thr-Gly-Phe-Leu-Ser-NH2) on Ser6 significantly increases BBB permeability (from 1.0 ± 0.2 μL min −1 •g −1 to 2.2 ± 0.2 μL min −1 •g −1 ), and enhances serum stability and the pain effect. 201 Further study has found that different sugar-modified peptides lead to different tissue distributions. Although glycosylation reduces the fat solubility of peptides, it increases the amphiphilicity of peptides, which is very important in promoting the transportation of peptides across the BBB through adsorption-mediated cell transport.…”

Synthesis and In Vitro Characterization of Glycopeptide Drug Candidates Related to PACAP1–23

“…, i.p. ) [ 40 , 41 , 42 , 43 , 44 , 45 ]. Our laboratory has extensively investigated glycosylation as a means to address the concerns of BBB permeability and stability for many endogenous peptides including opioid peptides, angiotensin 1 – 7 , and PACAP [ 46 , 47 , 48 , 49 , 50 ].…”