Objective/Rationale:
The mu opioid receptor (MOR) has long been proposed as an appealing target for managing levodopa-induced dyskinesia and therefore received attention from industry, which developed a series of MOR antagonists (to block its activity). As some of those antagonists were active and some were not, further characterization was undertaken in in vitro experiments. In an experiment on MOR, the supposedly antagonists were in fact separable into full antagonists, full agonists (which activate the receptor) and partial agonists. To our surprise, only the full agonists and the partial agonists provided an anti-dyskinetic benefit, therefore calling for a reappraisal of our current concept of MOR antagonization for levodopa-induced dyskinesia management.
Project Description:
Building upon this new knowledge, the MOR4LID research program will thus (i) test the origin of the anti-dyskinetic action of MOR manipulation and (ii) define the true nature of the required interaction with the MOR, i.e. antagonism or agonism. (iii) test antagonists of the kappa and delta receptors to get a comprehensive analysis. The project therefore aims to mechanistically validate the target on the basis of updated knowledge of drug-receptor functional relationships.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The project will either de-risk future development of drugs interacting with MOR for dyskinesia or will kill the target. This is a required step for deciding if the efforts are worth pursuing or if there is a dead end.
Anticipated Outcome:
The project will demonstrate what relationship with MOR is needed for anti-dyskinetic activity (i.e. antagonist or agonist) and where this action takes place in the brain (i.e. in the striatum or in the internal globus pallidus).
Final Outcome
Among the several targets that have been proposed for alleviating L-dopa-induced dyskinesia (LID), the mu opioid receptor has long been considered as a possibility when antagonizing (inhibiting) it. Several programs of medicinal chemistry were launched and mixed results were obtained when testing the produced new chemical entities into the gold standard experimental models of LID. Investigating further those mixed results, we found out that the compounds could be stratified differently depending of their mode of action. Using more recent functional assays, we found that agonizing (stimulating) the mu opioid receptor was improving LID, either trough oral or intracerebral administration (in the brain areas of interest). This project has therefore refined our understanding of the pathophysiology of LID and has allowed to clearly demonstrate that agonizing (instead of antagonizing) the mu opioid receptor decreases LID severity.