PDF(Pubmed)
Abstract：
Increased activity across corticostriatal glutamatergic synapses may contribute to L-DOPA-induced dyskinesia in Parkinson\'s disease. Given the weak efficacy and side-effect profile of amantadine, alternative strategies to reduce glutamate transmission are being investigated. Metabotropic glutamate receptor 4 (mGlu4) is a promising target since its activation would reduce glutamate release.
We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia.
The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats.
Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats.
This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.
We hypothesized that two mGlu4 positive allosteric modulators, Lu AF21934 ((1 S,2 R)-N1-(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide) and ADX88178 (5-Methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine), would provide relief in rat and primate models of L-DOPA-induced dyskinesia.
The ability of Lu AF21934 or ADX88178 to reverse pre-established dyskinesia was examined in L-DOPA-primed 6-hydroxydopamine-lesioned rats expressing abnormal involuntary movements (AIMs) or in 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated common marmosets expressing L-DOPA-induced dyskinesia. Additionally, the ability of Lu AF21934 to prevent the development of de novo L-DOPA-induced AIMs was explored in the 6-hydroxydopamine-lesioned rats.
Neither Lu AF21934 (10 or 30 mg/kg p.o.) nor ADX88178 (10 or 30 mg/kg p.o.) reduced pre-established AIMs in 6-hydroxydopamine-lesioned rats. Similarly, in L-DOPA-primed common marmosets, no reduction in established dyskinesia was observed with Lu AF21934 (3 or 10 mg/kg p.o.). Conversely, amantadine significantly reduced (>40%) the expression of dyskinesia in both models. Lu AF21934 also failed to suppress the development of AIMs in 6-hydroxydopamine-lesioned rats.
This study found no benefit of mGlu4 positive allosteric modulators in tackling L-DOPA-induced dyskinesia. These findings are concordant with the recent failure of foliglurax in phase II clinical trials supporting the predictive validity of these pre-clinical dyskinesia models, while raising further doubt on the anti-dyskinetic potential of mGlu4 positive allosteric modulators.
摘要：
■皮质纹状体谷氨酸能突触的活性增加可能导致帕金森病中L-DOPA诱导的运动障碍。考虑到金刚烷胺的弱疗效和副作用，正在研究减少谷氨酸传递的替代策略。代谢型谷氨酸受体4（mGlu4）是一个有前途的目标，因为它的激活会减少谷氨酸的释放。
■我们假设两个mGlu4正变构调节剂，LuAF21934((1S，2R）N1-（3,4-二氯苯基）环己烷-1,2-二甲酰胺）和ADX88178（5-甲基-N-（4-甲基嘧啶-2-基）-4-（1H-吡唑-4-基）噻唑-2-胺），将在L-DOPA诱导的运动障碍的大鼠和灵长类动物模型中提供缓解。
■在表达异常不自主运动（AIM）的L-DOPA引发的6-羟基多巴胺损伤的大鼠中，检查了LuAF21934或ADX88178逆转预先建立的运动障碍的能力，1,2,3,6-四氢吡啶（MPTP）处理的表达L-DOPA诱导的运动障碍的普通猴。此外,在6-羟基多巴胺损伤的大鼠中探索了LuAF21934预防从头L-DOPA诱导的AIM发展的能力。
■LuAF21934（10或30mg/kgp.o.）和ADX88178（10或30mg/kgp.o.）均未降低6-羟基多巴胺损伤大鼠中预先建立的AIM。同样，在L-DOPA引发的普通猿猴中，LuAF21934（3或10mg/kgp.o.）未观察到已建立的运动障碍减少。相反，在两种模型中,金刚烷胺显著降低(>40%)运动障碍的表达。LuAF21934也未能抑制6-羟基多巴胺损伤大鼠中AIM的发育。
■这项研究发现mGlu4正变构调节剂在解决L-DOPA诱导的运动障碍方面没有益处。这些发现与foliglurax在II期临床试验中最近的失败相一致，支持这些临床前运动障碍模型的预测有效性。同时进一步怀疑mGlu4正变构调节剂的抗运动障碍潜力。
■我们假设两个mGlu4正变构调节剂，LuAF21934((1S，2R）N1-（3,4-二氯苯基）环己烷-1,2-二甲酰胺）和ADX88178（5-甲基-N-（4-甲基嘧啶-2-基）-4-（1H-吡唑-4-基）噻唑-2-胺），将在L-DOPA诱导的运动障碍的大鼠和灵长类动物模型中提供缓解。
■在表达异常不自主运动（AIM）的L-DOPA引发的6-羟基多巴胺损伤的大鼠中，检查了LuAF21934或ADX88178逆转预先建立的运动障碍的能力，1,2,3,6-四氢吡啶（MPTP）处理的表达L-DOPA诱导的运动障碍的普通猴。此外,在6-羟基多巴胺损伤的大鼠中探索了LuAF21934预防从头L-DOPA诱导的AIM发展的能力。
■LuAF21934（10或30mg/kgp.o.）和ADX88178（10或30mg/kgp.o.）均未降低6-羟基多巴胺损伤大鼠中预先建立的AIM。同样，在L-DOPA引发的普通猿猴中，LuAF21934（3或10mg/kgp.o.）未观察到已建立的运动障碍减少。相反，在两种模型中,金刚烷胺显著降低(>40%)运动障碍的表达。LuAF21934也未能抑制6-羟基多巴胺损伤大鼠中AIM的发育。
■这项研究发现mGlu4正变构调节剂在解决L-DOPA诱导的运动障碍方面没有益处。这些发现与foliglurax在II期临床试验中最近的失败相一致，支持这些临床前运动障碍模型的预测有效性。同时进一步怀疑mGlu4正变构调节剂的抗运动障碍潜力。
