Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Ontario, Canada.
J Pharmacol Exp Ther. 2010 Jun;333(3):865-73. doi: 10.1124/jpet.110.166629. Epub 2010 Mar 15.
Long-term motor complications of dopamine replacement, such as L-DOPA-induced dyskinesia (LID) and reduced quality of L-DOPA action, remain obstacles in the treatment of Parkinson's disease. Dysfunctional glutamatergic neurotransmitter systems have been observed in both the untreated parkinsonian and dyskinetic states and represent novel targets for treatment. Here, we assess the pharmacokinetic profile and corresponding pharmacodynamic effects on behavior of the orally active, selective metabotropic glutamate receptor type 5 (mGlu5) antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) (as the hydrochloride salt) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned macaque. Six parkinsonian, MPTP-lesioned cynomolgus monkeys, with established LID, were administered acute challenges with MTEP (4.5-36 mg/kg p.o.) or vehicle, either alone or in combination with L-DOPA (33 +/- 1 mg/kg p.o.). Motor activity, parkinsonian disability, and dyskinesia were assessed for a 6-h period. Plasma drug levels were assessed by liquid chromatography-tandem mass spectrometry. MTEP had no antiparkinsonian action as monotherapy. However, administration of L-DOPA in combination with MTEP (36 mg/kg) reduced peak dose LID by 96%. Moreover, although total on-time (duration for which L-DOPA exerted an antiparkinsonian effect) was not significantly reduced, MTEP (36 mg/kg) reduced the duration of on-time with disabling LID by 70% compared with that for L-DOPA alone. These effects were associated with a peak plasma concentration of 20.9 microM and an area under the curve from 0 to 24 h of 136.1 h x microM (36 mg/kg). Although total on-time was not reduced, the peak antiparkinsonian benefit of l-DOPA/MTEP (36 mg/kg) was less than that with L-DOPA alone. Selective mGlu5 inhibitors may have significant potential to ameliorate dyskinesia, but care should be taken to ensure that such effects do not come at the expense of the peak antiparkinsonian benefit of L-DOPA.
长期多巴胺替代治疗的运动并发症，如左旋多巴诱导的运动障碍（LID）和左旋多巴作用质量降低，仍然是帕金森病治疗的障碍。在未经治疗的帕金森病和运动障碍状态下都观察到功能失调的谷氨酸能神经递质系统，它们是治疗的新靶点。在这里，我们评估了口服活性、选择性代谢型谷氨酸受体 5（mGlu5）拮抗剂 3-[(2-甲基-1,3-噻唑-4-基)乙炔基]吡啶（MTEP）（盐酸盐）在 1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤猕猴中的药代动力学特征及其对行为的相应药效学影响。6 只帕金森病、MPTP 损伤的食蟹猴，患有已确立的 LID，给予 MTEP（4.5-36mg/kg po）或载体单独或与左旋多巴（33 +/- 1mg/kg po）联合的急性挑战。在 6 小时期间评估运动活动、帕金森病残疾和运动障碍。通过液相色谱-串联质谱法评估血浆药物水平。MTEP 作为单药治疗没有抗帕金森病作用。然而，L-DOPA 与 MTEP（36mg/kg）联合给药可使峰值剂量 LID 减少 96%。此外，尽管总作用时间（左旋多巴发挥抗帕金森病作用的时间）没有显著减少，但与单独使用左旋多巴相比，MTEP（36mg/kg）减少了禁用 LID 的作用时间的 70%。这些作用与峰值血浆浓度 20.9μM 和 0 至 24 小时的 AUC 为 136.1 h x microM（36mg/kg）相关。尽管总作用时间没有减少，但 L-DOPA/MTEP（36mg/kg）的峰值抗帕金森病益处小于单独使用左旋多巴。选择性 mGlu5 抑制剂可能具有显著改善运动障碍的潜力，但应注意确保这些作用不会以牺牲左旋多巴的峰值抗帕金森病益处为代价。
