Abstract：
LY-404,039 is an orthosteric agonist at metabotropic glutamate 2 and 3 (mGlu 2/3 ) receptors, with a possible additional agonist effect at dopamine D 2 receptors. LY-404,039 and its pro-drug, LY-2140023, have previously been tested in clinical trials for psychiatric indications and could therefore be repurposed if they were shown to be efficacious in other conditions. We have recently demonstrated that the mGlu 2/3 orthosteric agonist LY-354,740 alleviated L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the 6-hydroxydopamine (6-OHDA)-lesioned rat without hampering the anti-parkinsonian action of L-DOPA. Here, we seek to take advantage of a possible additional D 2 -agonist effect of LY-404,039 and see if an anti-parkinsonian benefit might be achieved in addition to the antidyskinetic effect of mGlu 2/3 activation. To this end, we have administered LY-404,039 (vehicle, 0.1, 1 and 10 mg/kg) to 6-OHDA-lesioned rats, after which the severity of axial, limbs and oro-lingual (ALO) AIMs was assessed. The addition of LY-404,039 10 mg/kg to L-DOPA resulted in a significant reduction of ALO AIMs over 60-100 min (54%, P < 0.05). In addition, LY-404,039 significantly enhanced the antiparkinsonian effect of L-DOPA, assessed through the cylinder test (76%, P < 0.01). These results provide further evidence that mGlu 2/3 orthosteric stimulation may alleviate dyskinesia in PD and, in the specific case of LY-404,039, a possible D 2 -agonist effect might also make it attractive to address motor fluctuations. Because LY-404,039 and its pro-drug have been administered to humans, they could possibly be advanced to Phase IIa trials rapidly for the treatment of motor complications in PD.
摘要：
LY-404,039是代谢型谷氨酸2和3（mGlu2/3）受体的正位激动剂，对多巴胺D2受体有可能的额外激动剂作用。LY-404,039及其前药,LY-2140023先前已在临床试验中进行了精神病学适应症的测试，因此如果证明它们在其他条件下有效，则可以重新利用。我们最近证明，mGlu2/3正位激动剂LY-354,740减轻了6-羟基多巴胺（6-OHDA）损伤的大鼠中L-3,4-二羟基苯丙氨酸（L-DOPA）诱导的异常不自主运动（AIM），而不妨碍L-DOPA的抗帕金森病作用。这里,我们试图利用LY-404,039可能的额外D2激动剂作用,看看除了mGlu2/3激活的抗运动障碍作用外,是否还可能获得抗帕金森病的益处.为此,我们已经管理了LY-404,039(车辆，0.1、1和10mg/kg）对6-OHDA损伤的大鼠，在此之后，轴向的严重性，评估四肢和口舌（ALO）AIM。向L-DOPA中添加LY-404,03910mg/kg导致ALOAIM在60-100分钟内显着减少（54％，P<0.05)。此外,LY-404,039显着增强了L-DOPA的抗帕金森病作用，通过气缸测试评估(76%，P<0.01)。这些结果提供了进一步的证据，表明mGlu2/3正位刺激可以减轻PD的运动障碍，在LY-404,039的特定情况下,可能的D2激动剂效应也可能使其对解决运动波动具有吸引力。因为LY-404,039和它的前药已经被用于人类,他们可能会迅速推进到治疗PD运动并发症的IIa期试验.
