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

Mitchell J Bartlett,Omar S Mabrouk,Scott J Sherman,Kate L Parent,Robin Polt,Michael L Heien,Lajos Szabò,Jean M Bidlack,Robert T Kennedy,Andrew J Flores,Torsten Falk

doi:10.3390/ijms22010020

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.

Highlights

The opioid neurotransmission system is prominent in the vertebrate basal ganglia
This is true for a disorder manifested by abnormal involuntary movements (AIMs) that develops after prolonged DA replacement therapy with levodopa (L-DOPA) in individuals with Parkinson’s disease (PD), L-DOPA-induced dyskinesia (LID) [2]
central nervous system (CNS) penetration of the glycopeptide BBI-11008 (Figure 1A), a DOR agonist, was verified with microdialysis in the dorsolateral striatum (DLS) of male rats followed by liquid chromatography-mass spectrometry (LC-MS)

Summary

Introduction

Endogenous opioid peptides and their precursors are expressed at high levels within the basal ganglia, where they are modulators of dopamine (DA) and glutamate neurotransmission [1] This makes the opioid system of interest for Parkinson’s disease (PD), where death of dopaminergic neurons in the substantia nigra and loss of striatal DA are central to the hypokinetic movement symptoms. The importance of the opioid neurotransmitter system has been further established by positron emission tomography studies which have revealed abnormalities in the expression of striatal opioid receptors in patients with LID [21] This suggests that increased opioid neurotransmission, especially MOR overactivity, may be associated with the pathophysiology of LID. Our understanding of the opioid system in the context of LID has been further complicated by the failure of two pan-opioid receptor antagonists without subtype-selectivity, naltrexone and naloxone, in clinical trials [22,23]

Methods

Results

Conclusion