Advanced Parkinson’s disease (PD) is often complicated by the occurrence of dyskinesia, motor fluctuations and psychosis. To this day, few treatment options are available for each of these phenomena, and they are at times not effective or elicit adverse events, leaving some patients short of therapeutic options. We have recently shown that positive allosteric modulation of metabotropic 2 (mGlu₂) receptors with the prototypical positive allosteric modulator (PAM) LY-487,379 is efficacious at alleviating both dyskinesia and psychosis-like behaviours (PLBs), while simultaneously enhancing the anti-parkinsonian action of L-3,4-dihydroxyphenylalanine (L-DOPA), in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset. Here, we assessed the effects of CBiPES, a mGlu₂ PAM derived from LY-487,379, but with improved pharmacokinetic properties. Six MPTP-lesioned marmosets with reproducible dyskinesia and PLBs were administered L-DOPA in combination with vehicle or CBiPES (0.1, 1 and 10 mg/kg), after which their behaviour was rated. CBiPES 10 mg/kg reduced global dyskinesia by 60% (P < 0.0001), while peak dose dyskinesia was reduced by 66% (P < 0.001), compared to L-DOPA/vehicle. CBiPES 10 mg/kg also diminished global PLBs by 56% (P < 0.0001), while peak dose PLBs were reduced by 64% (P < 0.001), compared to L-DOPA/vehicle. Lastly, CBiPES enhanced the anti-parkinsonian action of L-DOPA, by reducing global parkinsonian disability by 43% (P < 0.01), compared to L-DOPA/vehicle. Our results provide further evidence that mGlu₂ positive allosteric modulation may be an approach that could be efficacious for the treatment of dyskinesia, psychosis and motor fluctuations in PD.

晚期帕金森病 (PD) 常因运动障碍、运动波动和精神病的发生而复杂化。直到今天，这些现象中的每一种都几乎没有可用的治疗选择，而且它们有时无效或引发不良事件，使一些患者缺乏治疗选择。我们最近表明，使用原型正变构调节剂 (PAM) LY-487,379 对代谢型 2 (mGlu ₂ ) 受体进行正变构调节可有效缓解运动障碍和精神病样行为 (PLB)，同时增强抗帕金森病L-3,4-二羟基苯丙氨酸 (L-DOPA) 在 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 损伤狨猴中的作用。在这里，我们评估了 CBiPES（一种 mGlu ₂PAM 源自 LY-487,379，但具有改进的药代动力学特性。六只 MPTP 损伤的狨猴具有可重复的运动障碍和 PLB，与载体或 CBiPES（0.1、1 和 10 mg/kg）联合施用 L-DOPA，然后对它们的行为进行评级。与左旋多巴/车辆相比， CBiPES 10 mg/kg 将整体运动障碍减少了 60%（P  < 0.0001），而峰值剂量运动障碍减少了 66%（P  < 0.001）。与左旋多巴/车辆相比， CBiPES 10 mg/kg 还使全球 PLB 减少了 56%（P  < 0.0001），而峰值剂量 PLB 减少了 64%（P  < 0.001）。最后，CBiPES 增强了 L-DOPA 的抗帕金森病作用，将全球帕金森病残疾减少了 43%（P < 0.01)，与左旋多巴/车辆相比。我们的研究结果进一步证明 mGlu ₂正变构调节可能是一种有效治疗 PD 运动障碍、精神病和运动波动的方法。