Shaqfah Judy, Bédard Dominique, Nuara Stephen G, Gourdon Jim C, Hamadjida Adjia, Gaudette Fleur, Beaudry Francis, Huot Philippe
Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada.
Comparative Medicine and Animal Resource Centre, McGill University, Montreal, QC, Canada.
Eur J Pharmacol. 2025 Oct 15;1005:178031. doi: 10.1016/j.ejphar.2025.178031. Epub 2025 Aug 5.
AZD8529 is a highly selective metabotropic glutamate 2 (mGlu) receptor positive allosteric modulator (PAM) that has undergone clinical trials for schizophrenia and smoking cessation. Previously, we demonstrated that the selective mGlu receptor PAMs LY-487,379, CBiPES, and biphenylindanone A (BINA) alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia and psychosis-like behaviours (PLBs) in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned marmoset model of Parkinson's disease (PD). However, these drugs are not clinical candidates because of their pharmacological properties, contrary to AZD8529 which could be repurposed if pre-clinically efficacious. To assess the effect of AZD8529 on L-DOPA-induced dyskinesia and PLBs in the MPTP-lesioned marmoset, we first determined the pharmacokinetic (PK) profile of AZD8529 in this species to inform dose selection such that drug plasma levels were clinically relevant. Then, MPTP-lesioned animals were treated with L-DOPA with either vehicle or AZD8529 (0.1, 0.3, 1, and 10 mg/kg). The results showed a reduction in global dyskinesia severity (up to 70 %, P < 0.001), and in duration of on-time with disabling dyskinesia (up to 97 %, P < 0.001) when compared to L-DOPA/vehicle. Similarly, there was a reduction in global PLB severity (up to 64 %, P < 0.001), and in duration of on-time with disabling PLBs (up to 94 %, P < 0.001) when compared to L-DOPA/vehicle. Additionally, AZD8529 increased the duration of the anti-parkinsonian action of L-DOPA at doses of 0.3 mg/kg and above (up to 29 %, P < 0.05). Our results further demonstrate the potential of AZD8529 and mGlu receptor positive allosteric modulation for alleviating L-DOPA-induced dyskinesia and PLBs while amplifying the therapeutic efficacy of L-DOPA.
AZD8529是一种高选择性的代谢型谷氨酸2（mGlu）受体正向变构调节剂（PAM），已针对精神分裂症和戒烟进行了临床试验。此前，我们证明了选择性mGlu受体PAMs LY-487,379、CBiPES和联苯茚满酮A（BINA）在1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）损伤的帕金森病（PD）狨猴模型中减轻了左旋多巴（L-DOPA）诱导的运动障碍和类精神病行为（PLB）。然而，由于它们的药理学特性，这些药物并非临床候选药物，这与AZD8529相反，如果临床前有效，AZD8529可以被重新利用。为了评估AZD8529对MPTP损伤狨猴中L-DOPA诱导的运动障碍和PLB的影响，我们首先确定了AZD8529在该物种中的药代动力学（PK）特征，以指导剂量选择，使药物血浆水平具有临床相关性。然后，用L-DOPA加溶剂或AZD8529（0.1、0.3、1和10mg/kg）治疗MPTP损伤的动物。结果显示，与L-DOPA/溶剂相比，整体运动障碍严重程度降低（高达70%，P<0.001），致残性运动障碍的开启时间持续缩短（高达97%，P<0.001）。同样，与L-DOPA/溶剂相比，整体PLB严重程度降低（高达64%，P<0.001），致残性PLB的开启时间持续缩短（高达94%，P<0.001）。此外，在0.3mg/kg及以上剂量时，AZD8529增加了L-DOPA的抗帕金森作用持续时间（高达29%，P<0.05）。我们的结果进一步证明了AZD8529和mGlu受体正向变构调节在减轻L-DOPA诱导的运动障碍和PLB同时增强L-DOPA治疗效果方面的潜力。
