Endogenous activation of the Delta opioid receptor (DOR) serves as a compensatory mechanism to alleviate Parkinson’s disease (PD) symptoms. However, DOR-mediated convulsions have hindered DOR agonist drug development. This project aims to validate the DOR in as a target for PD therapy using a novel strategy termed G protein coupled receptor ligand bias. We hypothesize this approach will provide a DOR ligand effective in suppressing motor symptoms associated with PD, while devoid of the target-based convulsant liability associated with DOR agonists.
We will utilize an MPTP pre-clinical model to validate ligand bias as an approach to treat PD. We have discovered that beta-arrestin2, a DOR-interacting protein, promotes convulsions, while G protein coupling mediates beneficial CNS pharmacology such as antidepressant efficacy. The project consists of the following experiments:
We will determine if biased DOR drugs could be useful therapeutics for PD without inducing unwanted side-effects such as convulsions. If these validation studies prove successful we will test Trevena’s G pathway biased compounds to demonstrate efficacy and lack of convulsion liability in PD models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Novel mechanism drugs which can serve as significant Symptoms & Side Effects therapeutics will offer patients more options to manage their PD. There is evidence for DOR actions at the critical sites of PD pathogenesis, as the DOR is widely expressed in the brain at sites where there is dopaminergic neuronal loss. In addition, DOR agonists may also be effective for treatment of non motor symptoms associated with PD, such as anxiety, depression, pain and urinary incontinence. Success in our project will result in a “G protein biased” DOR drug which engages G protein coupling, but does not recruit beta-arrestins and deliver an effective therapeutic devoid of side-effects.
If successful, this work should identify the DOR as a promising drug-discovery target for therapeutics to treat PD. The follow-on to this work will be initiating a drug discovery and development project to identify a novel therapy for PD, targeting the DOR.
Acute administration of novel compounds targeting the delta-opioid receptor (DOR) reversed motor impairments in two preclinical models of Parkinson’s disease (PD). We demonstrated that two DOR ligands reversed akinesia/bradykinesia in both the haloperidol and 6-OHDA hemilesioned pre-clinical models of PD. The key challenge of developing therapeutics targeting the DOR is that activation of the DOR can cause seizure. These ligands are “biased”, engaging the beneficial motor control responses of the DOR while avoiding DOR signals linked to seizure liability. In addition, the novel compounds significantly up-regulated brain derived neurotrophic factor mRNA expression in pre-clinical model brain striatum, a key site of neuronal disruption in PD, suggesting neuroprotective potential for these ligands that could slow disease progression. These results demonstrate the potential for targeting the DOR with biased ligands and support further testing of this class of molecule for therapeutic utility in PD.