l-DOPA is the gold-standard pharmacotherapy for treatment of Parkinson's disease (PD) but can lead to the appearance of troubling dyskinesia which are attributable to 'false neurotransmitter' release of dopamine by serotonergic neurons. Reducing the activity of these neurons diminishes l-DOPA-induced dyskinesia (LID), but there are currently no clinically approved selective, high efficacy 5-HT1A receptor agonists. Here we describe the effects of NLX-112, a highly selective and efficacious 5-HT1A receptor agonist, on LID in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated marmosets, a non-human primate model of PD. NLX-112 exhibited modest plasma half-life (~2h) and marked plasma protein binding (96%). When administered to parkinsonian marmosets with l-DOPA (7 mg/kg p.o.), NLX-112 (0.025, 0.1 and 0.4 mg/kg p.o.) reduced LID scores at early time-points after administration, whilst only minimally interfering with the l-DOPA-induced reversal of motor disability. In contrast, the prototypical 5-HT1A receptor agonist, (+)8-OH-DPAT (0.6 and 2 mg/kg p. o.), reduced LID but also abolished l-DOPA's anti-disability activity. Administered by itself, NLX-112 (0.1, 0.2 mg/kg p.o.) produced very little dyskinesia or locomotor activity, but reduced motor disability scores by about half the extent elicited by l-DOPA, suggesting that it may have motor facilitation effects of its own. Both NLX-112 and (+)8-OH-DPAT induced unusual and dose-limiting behaviors in marmoset that resembled 'serotonin behavioral syndrome' observed previously in rat. Overall, the present study showed that NLX-112 has anti-LID activity at the doses tested as well as reducing motor disability. The data suggest that additional investigation of NLX-112 is desirable to explore its potential as a treatment for PD and PD-LID.

中文翻译：

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选择性5-HT1A受体激动剂NLX-112在MPTP处理的mar猴中具有抗运动障碍和抗帕金森病样作用。

l-DOPA是治疗帕金森氏病（PD）的金标准药物疗法，但会导致令人不安的运动障碍，这归因于血清素能神经元“多巴胺的假神经递质”释放。降低这些神经元的活性可减少1-DOPA诱导的运动障碍（LID），但目前尚无临床认可的选择性，高效5-HT1A受体激动剂。在这里，我们描述了NLX-112（一种高度选择性和有效的5-HT1A受体激动剂）对1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）处理的猴（非-PD的人类灵长类动物模型。NLX-112表现出适度的血浆半衰期（〜2h）和明显的血浆蛋白结合（96％）。当与l-DOPA（7 mg / kg po）一起用于帕金森0.0猴时，NLX-112（0.025、0.1和0.4 mg / kg po ）在给药后的早期时间点降低了LID评分，而仅对I-DOPA引起的运动障碍逆转产生最小的干扰。相反，典型的5-HT1A受体激动剂（+）8-OH-DPAT（0.6和2 mg / kg po）降低了LID，但也废除了1-DOPA的抗残疾活性。单独服用NLX-112（0.1，0.2 mg / kg，口服）产生很少的运动障碍或运动功能，但将运动障碍评分降低了1-DOPA引起的程度的一半，这表明它可能具有其运动促进作用。拥有。NLX-112和（+）8-OH-DPAT都在mar猴中引起异常和剂量限制的行为，类似于先前在大鼠中观察到的“ 5-羟色胺行为综合症”。总体，本研究表明，NLX-112在所测试的剂量下具有抗LID活性，并能减少运动障碍。数据表明，需要进一步研究NLX-112，以探索其作为治疗PD和PD-LID的潜力。