DPI-289, a novel mixed delta opioid agonist / mu opioid antagonist (DAMA), has L-DOPA-sparing potential in Parkinson's disease
Autor: | Paula Ravenscroft, Susan H. Fox, Michael Hill, Tom H. Johnston, Jonathan M. Brotchie, Patrick A. Howson, Eboo Versi, Bruce E. Reidenberg, Ronald Corey |
---|---|
Rok vydání: | 2018 |
Předmět: |
Male
0301 basic medicine Agonist Dyskinesia Drug-Induced Parkinson's disease medicine.drug_class Movement Narcotic Antagonists Guinea Pigs Receptors Opioid mu Pharmacology Piperazines Levodopa Rats Sprague-Dawley Mice 03 medical and health sciences Cellular and Molecular Neuroscience Adrenergic Agents Vas Deferens 0302 clinical medicine Parkinsonian Disorders Opioid receptor Receptors Opioid delta medicine Animals Oxidopamine Dose-Response Relationship Drug business.industry Parkinsonism Dopaminergic Antagonist Parkinson Disease medicine.disease Abnormal involuntary movement nervous system diseases Analgesics Opioid Mice Inbred C57BL Disease Models Animal 030104 developmental biology Dyskinesia Benzamides Macaca Female medicine.symptom business 030217 neurology & neurosurgery |
Zdroj: | Neuropharmacology. 131:116-127 |
ISSN: | 0028-3908 |
Popis: | L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (Ki: 0.73 nM); mu antagonist (Ki: 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease. |
Databáze: | OpenAIRE |
Externí odkaz: |