Montreal Neurological Institute-Hospital (The Neuro), 3801 University St, Montreal, QC, H3A 2B4, Canada.
Comparative Medicine & Animal Resource Centre, McGill University, Montreal, QC, Canada.
Naunyn Schmiedebergs Arch Pharmacol. 2023 Oct;396(10):2347-2355. doi: 10.1007/s00210-023-02587-2. Epub 2023 Jul 6.
LY-404,039 is an orthosteric agonist of metabotropic glutamate 2 and 3 receptors (mGluR) that may harbour additional agonist effect at dopamine D receptors. LY-404,039 and its pro-drug, LY-2140023, have previously entered clinical trials as treatment options for schizophrenia. They could therefore be repurposed, if proven efficacious, for other conditions, notably Parkinson's disease (PD). We have previously shown that the mGluR orthosteric agonist LY-354,740 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. Unlike LY-404,039, LY-354,740 does not stimulate dopamine D receptors, suggesting that LY-404,039 may elicit broader therapeutic effects in PD. Here, we sought to investigate the effect of this possible additional dopamine D-agonist action of LY-404,039 by assessing its efficacy on dyskinesia, PLBs and parkinsonism in the MPTP-lesioned marmoset. We first determined the pharmacokinetic profile of LY-404,039 in the marmoset, in order to select doses resulting in plasma concentrations known to be well tolerated in the clinic. Marmosets were then injected L-DOPA with either vehicle or LY-404,039 (0.1, 0.3, 1 and 10 mg/kg). The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of global dyskinesia (by 55%, P < 0.01) and PLBs (by 50%, P < 0.05), as well as reduction of global parkinsonism (by 47%, P < 0.05). Our results provide additional support of the efficacy of mGluR orthosteric stimulation at alleviating dyskinesia, PLBs and parkinsonism. Because LY-404,039 has already been tested in clinical trials, it could be repurposed for indications related to PD.
LY-404,039 是代谢型谷氨酸 2 和 3 受体(mGluR)的正构激动剂,可能在多巴胺 D 受体上具有额外的激动作用。LY-404,039 和其前药 LY-2140023 此前已作为精神分裂症的治疗选择进入临床试验。因此,如果被证明有效,它们可以被重新用于其他疾病,特别是帕金森病(PD)。我们之前已经表明,mGluR 正构激动剂 LY-354,740 减轻了 1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)损伤的狨猴中的 L-3,4-二羟基苯丙氨酸(L-DOPA)诱导的运动障碍和精神病样行为(PLBs)。与 LY-404,039 不同,LY-354,740 不刺激多巴胺 D 受体,这表明 LY-404,039 可能在 PD 中产生更广泛的治疗效果。在这里,我们试图通过评估 LY-404,039 对 MPTP 损伤的狨猴运动障碍、PLBs 和帕金森病的疗效,来研究其可能的多巴胺 D 激动作用。我们首先确定了 LY-404,039 在狨猴中的药代动力学特征,以便选择产生已知在临床中可耐受的血浆浓度的剂量。然后,狨猴接受 L-DOPA 与载体或 LY-404,039(0.1、0.3、1 和 10mg/kg)一起注射。将 LY-404,039 10mg/kg 加入 L-DOPA 中,可显著减少整体运动障碍(减少 55%,P<0.01)和 PLBs(减少 50%,P<0.05),以及减少整体帕金森病(减少 47%,P<0.05)。我们的结果提供了更多支持 mGluR 正构刺激缓解运动障碍、PLBs 和帕金森病的疗效的证据。因为 LY-404,039 已经在临床试验中进行了测试,所以它可以被重新用于与 PD 相关的适应症。