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Article

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

1
Department of Neurology, College of Medicine, University of Arizona, Tucson, AZ 85724, USA
2
Department of Chemistry, University of Michigan, Ann Arbor, MI 48109, USA
3
Department of Chemistry & Biochemistry, University of Arizona, Tucson, AZ 85721, USA
4
Graduate Interdisciplinary Program in Physiological Sciences, University of Arizona, Tucson, AZ 85724, USA
5
Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
6
Department of Pharmacology, University of Arizona, Tucson, AZ 85724, USA
*
Author to whom correspondence should be addressed.
Current Address: Biogen Clinical Sciences Biomarkers, 225 Binney Street, Cambridge, MA 02142, USA.
Int. J. Mol. Sci. 2021, 22(1), 20; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010020
Received: 20 November 2020 / Revised: 17 December 2020 / Accepted: 18 December 2020 / Published: 22 December 2020
(This article belongs to the Special Issue Peptides for Health Benefits 2020)
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. View Full-Text
Keywords: L-DOPA; Parkinson’s disease; basal ganglia L-DOPA; Parkinson’s disease; basal ganglia
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MDPI and ACS Style

Bartlett, M.J.; Mabrouk, O.S.; Szabò, L.; Flores, A.J.; Parent, K.L.; Bidlack, J.M.; Heien, M.L.; Kennedy, R.T.; Polt, R.; Sherman, S.J.; Falk, T. The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia. Int. J. Mol. Sci. 2021, 22, 20. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010020

AMA Style

Bartlett MJ, Mabrouk OS, Szabò L, Flores AJ, Parent KL, Bidlack JM, Heien ML, Kennedy RT, Polt R, Sherman SJ, Falk T. The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia. International Journal of Molecular Sciences. 2021; 22(1):20. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010020

Chicago/Turabian Style

Bartlett, Mitchell J., Omar S. Mabrouk, Lajos Szabò, Andrew J. Flores, Kate L. Parent, Jean M. Bidlack, Michael L. Heien, Robert T. Kennedy, Robin Polt, Scott J. Sherman, and Torsten Falk. 2021. "The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia" International Journal of Molecular Sciences 22, no. 1: 20. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010020

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