Objective/Rationale:
Nearly all Parkinson's patients will eventually be treated with levodopa. However, the majority of patients will eventually develop disabling side effects known as levodopa-induced dyskinesia which causes disruptive involuntary movements of the body. To date, there is no effective medical treatment for levodopa-induced dyskinesia other than surgical intervention. The objective of this proposal is to develop new compounds and to test them in pre-clinical models of levodopa-induced dyskinesia.
Project Description:
Certain naturally occurring brain chemicals called opioid peptides are known to be important in controlling the motor pathways involved in levodopa-induced dyskinesia. Drugs that mimic these normal peptides could be useful therapeutic agents but are limited by their ability to enter the brain through the blood/brain barrier. We have discovered methods to effectively deliver these peptides to the target regions of the brain using a chemical modification process known as “glycosylation.” Our objective is to further develop these glycosylated peptide compounds and to test them for their ability to penetrate the blood brain barrier and to eliminate levodopa-induced dyskinesia in pre-clinical models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Parkinson's disease presents a therapeutic challenge, because medication adjustments must be fine-tuned to avoid that threshold which causes disruptive involuntary movements. Novel opioid-peptide compounds could provide an important non-dopaminergic treatment for Parkinson's disease, with a high likelihood of reduced kinetic side effects. Our combined efforts should set the stage for development of a new class of therapeutic agents for Parkinson's disease with the aim of stopping troublesome dyskinesias.
Anticipated Outcomes:
- We will produce glycosylated opioid peptides relevant to the areas of the brain affected by PD
- We will have demonstrated that compounds reach the intended area of the brain when given as a drug, solving the blood-brain-barrier problem with glycosylated peptides
- We will have tested new compounds in pre-clinical models of Parkinson disease identifying a lead compound for further development
Final Outcome
We have synthesized the glycosylated delta-opioid receptor agonist gDeltorphin. gDeltorphin reduced one type of levodopa-induced abnormal involuntary movements (AIMs), the locomotor AIMs, while not affecting other types of AIMs that are correlates of dyskinesia, such as jerkiness or facial twitching. Brain uptake of gDeltorphin was verified with microdialysis, a technique that allows us to quantify the test drugs in the brain area of interest (the striatum). This shows that glycosylation can increase the brain penetrance of a drug that otherwise cannot enter the brain well. We also have synthesized four mu opioid receptor antagonists (gCTAP2-5) that differ in the type of glycosylation, and the unglycosylated parent compound CTAP, a known highly specific mu opioid receptor antagonist with proven brain penetrance. Behavioral testing of all four novel mu-opioid antagonist glycopeptides (gCTAP 2-5) and of CTAP has not shown significant effects on any AIMs in our preclinical model. A functional test evaluating the ability to block the effect of morphine in a pain test indicate that CTAP and the four glycopeptide analogues are indeed able to act as mu opioid receptor antagonists in the brain. Our data indicate that full highly specific mu opioid receptor antagonists might not be reliable therapeutic drug candidates for levodopa-induced dyskinesia.
Researchers
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Scott J. Sherman, MD, PhD