The Delta-Specific Opioid Glycopeptide BBI-11008: CNS Penetration and Behavioral Analysis in a Preclinical Model of Levodopa-Induced Dyskinesia
Abstract
:1. Introduction
2. Results
2.1. BBI-11008 Reached High Concentrations in the Rodent Dorsolateral Striatum after Systemic Injection
2.2. Verification of the 6-Hydroxydopamine-Lesion
2.3. Establishment of Limb, Axial, Orolingual and Locomotor Abnormal Involuntary Movements
2.4. BBI-11008 Reduced L-DOPA-Induced Locomotor Abnormal Involuntary Movements
2.5. BBI-11008 Did Not Affect Either the Anti-Dyskinetic Nor the Pro-Parkinsonian Activity of MK-801
3. Discussion
4. Materials and Methods
4.1. Synthesis of BBI-11008
4.2. Animals for Microdialysis
4.3. Animals for L-DOPA-Induced Dyskinesia Model
4.4. In Vivo Microdialysis
4.5. Unilateral 6-Hydroxydopamine-Lesion Rat Model of Parkinson’s Disease
4.6. Amphetamine-Induced Rotation Test
4.7. Induction of L-DOPA-Induced Dyskinesia in Unilateral 6-OHDA-Lesioned Rats
4.8. Behavioral Analysis in the L-DOPA-Induced Dyskinesia Rat Model
4.9. Measurement of Striatal Dopamine Content
4.10. Western Analysis of Striatal Tyrosine Hydroxylase Content
4.11. Data Analysis
Author Contributions
Funding
Conflicts of Interest
Abbreviations
[3H] | Tritium |
6-OHDA | 6-hydroxydopamine |
AIMs | Abnormal involuntary movements |
ANOVA | Analysis of variance |
AIR | Amphetamine-induced rotation |
BBB | Blood-brain barrier |
BBI-11008 | glycosylated δ-opioid receptor agonist |
βA | Beta Actin |
CHO | Chinese hamster ovary |
CNS | Central nervous system |
DA | Dopamine |
DMF | Dimethylformamide |
DMSO | dimethylsulfoxide |
DCM | Dichloromethane |
DIC | N,N′-Diisopropylcarbodiimide |
DOR | δ opioid receptor |
DLS | Dorsolateral striatum |
Fmoc | fluorenylmethoxycarbonyl |
GABA | gamma-aminobutyric acid |
Gal | Galactose |
Glc | Glucose |
HPLC-EC | High performance liquid chromatography with electrochemical detection |
HOBT | Hydroxybenzotriazole |
HRP | Horseradish peroxidase |
I | Intact hemisphere |
i.p. | Intraperitoneal |
LAO | Limb, Axial, and Orolingual |
LC-MS | Liquid chromatography with mass spectrometry detection |
L-DOPA | Levodopa, L-3,4-dihydroxyphenylalanine |
LID | L-DOPA-Induced Dyskinesia |
KOR | κ Opioid Receptor |
LX | Lesioned hemisphere |
Man | Mannose |
MSNs | Medium spiny neurons |
MK-801 | Dizocilpine, N-methyl-D-aspartate receptor antagonist |
MMP-2200 | Lactomorphin, glycosylated mixed μ/δ-opioid receptor agonist |
MOR | μ opioid receptor |
NIH | National Institute of Health |
NIDA | National Institute on Drug Abuse |
NMDA | N-methyl-D-aspartate |
NMP | N-methylpyrrolidinone |
Nle | Nor-Leucine |
Nva | Nor-Valine |
PD | Parkinson’s disease |
PPE-A, Penk | Preproenkephalin-A |
PPE-B, Pdyn | Preproenkephalin-B |
TH | Tyrosine Hydroxylase |
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Sequence | % Inhibition at DOR 100 nM, 1 µM | % Inhibition at MOR 100 nM, 1 µM | Ki DOR (nM) | Ki MOR (nM) | Ki KOR (nM) | |
---|---|---|---|---|---|---|
DPDPE | 72, 84 | 23, 62 | 4.3 | 180 | ||
H2N-YaFDVVG-S(β-D-Glc)-G | LSZ-27 | 51, 67 | 6, 48 | 33 | 570 | |
H2N-YmFHLM-S(β-D-Glc) | BBI-11001 | 72, 84 | 63, 89 | |||
H2N-YaFHLA-S(β-D-Glc) | BBI-11002 | 55, 77 | 82, 97 | |||
H2N-YmFHLMT-(β-D-Glc) | BBI-11003 | 75, 83 | 57, 89 | |||
H2N-YaFHLAT-(β-D-Glc) | BBI-11004 | 61, 76 | 88, 98 | |||
H2N-YaFE-Nva-Nva-S-(β-D-Glc) | BBI-11005 | 65, 80 | 11, 44 | 20 | 710 | 5.3% |
H2N-YaFE-Nle-Nle-S-(β-D-Glc) | BBI-11006 | 66, 81 | 7, 42 | 11 | 820 | 38% |
H2N-YaFE-Nva-Nva-T-(β-D-Glc) | BBI-11007 | 64, 80 | 13, 36 | 16 | 1300 | 0% |
H2N-YaFE-Nle-Nle-T-(β-D-Glc) | BBI-11008 | 74, 84 | 7, 37 | 14 | 1100 | 2.9% |
H2N-YaFE-Nle-Nle-T | BBI-11009 | 11 | 510 | 3.7% | ||
H2N-YaFEII-T-(β-D-Glc) | BBI-11014 | 80 | 2600 | 36% | ||
H2N-YaFEVV-S-(β-D-Glc) | BBI-11015 | 320 | 1500 | 0% | ||
H2N-YaFE-Nle-Nle-S-(βGlc-βGal) | BBI-11021 | 17 | 1500 | 23% | ||
H2N-YaFEVV-S-(βGlc-βGal) | BBI-11022 | 3600 | 1000 | 71% | ||
H2N-YaFE-Nle-Nle-S-(α-D-Man) | BBI-11023 | 8.2 | 840 | 4.7% | ||
H2N-YaFE-Nva-Nva-S-(α-D-Man) | BBI-11024 | 13 | 990 | 0% | ||
H2N-YaFE-Nle-Nle-S-(βGlc-βGlc) | BBI-11025 | 13 | 1200 | 46% | ||
H2N-YaFE-Ile-Ile-S-(βGlc-βGlc) | BBI-11026 | 61 | 3000 | 2.7% |
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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.; et al. 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://doi.org/10.3390/ijms22010020
Bartlett MJ, Mabrouk OS, Szabò L, Flores AJ, Parent KL, Bidlack JM, Heien ML, Kennedy RT, Polt R, Sherman SJ, et al. 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://doi.org/10.3390/ijms22010020
Chicago/Turabian StyleBartlett, 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 et al. 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://doi.org/10.3390/ijms22010020