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Pharmacological actions of a novel and highly selective D3 dopamine receptor agonist, ML417, in a rodent model of Parkinson’s disease

Since its first use in treating Parkinson’s disease (PD), L‐DOPA has remained the gold standard of therapy for this disorder, defined by the progressive degeneration of dopaminergic neurons in the CNS leading to profound bradykinesia and tremor. The efficacy of L‐DOPA wanes over time and is associated with increasing side effects, including motor fluctuations and dyskinesias. Several dopaminergic agonists have also been introduced to treat PD, including pramipexole and ropinirole, which exhibit fewer motor side effects but are associated with impulse control disorders such as excessive gambling and hypersexuality. Notably, the dopamine receptor subtype(s) mediating the therapeutic actions and/or side effects in PD therapy remain unknown. However, the preference of pramipexole and ropinirole for the D3 dopamine receptor (D3R) suggests the involvement of this subtype, although these drugs also activate the D2R at therapeutic doses. Importantly, no drug currently employed to treat PD alters the course of the disease and the discovery of neuroprotective agents remain an unmet need in PD therapeutics. Recently, we discovered a novel, potent and highly selective agonist for the D3R, ML417, that is brain penetrant and was found to protect against 6‐OHDA‐induced neurodegeneration of dopaminergic neurons (Moritz et al., J. Med. Chem. 63: 5526, 2020). In the current study, we used ML417 to probe the role of the D3R in a rat model of PD. We initially sought to investigate the role of the D3R in ameliorating bradykinesia in a hemi‐parkinsonian rat model induced by 6‐OHDA infusion into the medial forebrain bundle. Using a validated cylindrical treadmill test of locomotion, doses of ML417 up to 20 mg/kg had no effect on improving impairments in walking as assessed by step counts in the hemi‐parkinsonian rats. In contrast, administration of L‐DOPA (6 mg/kg) significantly improves locomotion in the same model. Further, pretreatment with a D3R‐selective antagonist, SB277011A (30 mg/kg), did not attenuate the effects of L‐DOPA in reducing bradykinesia. These results suggest that the D3R does not mediate the anti‐bradykinetic effects of current PD therapeutics. However, we hypothesize that D3R stimulation may be beneficial for the treatment of L‐DOPA‐induced dyskinesias (LIDs) in PD. To test this, we used a chronic L‐DOPA administration paradigm (12 mg/kg/day for 7 days) to induce dyskinesias in the hemi‐parkinsonian rats. Subsequently, the effects of ML417 and SB277011A were assessed in these animals using an abnormal involuntary movement (AIMs) scoring method. Pretreatment with a single dose of ML417 (20 mg/kg) significantly reduced the intensity and duration of dyskinesias promoted with a single dose of L‐DOPA (6 mg/kg). Further, co‐administration of SB277011A (30 mg/kg) with ML417 attenuated the anti‐dyskinetic effects of ML417, suggesting that the benefit is D3R‐mediated. Overall, this study implies that D3R stimulation has no therapeutic effect on bradykinesia in PD, however, it may be beneficial in treating dyskinesias arising from L‐DOPA therapy.