Toronto Western Research Institute, MCL 11-419, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON, Canada M5T 2S8.
J Pharmacol Exp Ther. 2011 Oct;339(1):2-8. doi: 10.1124/jpet.111.184093. Epub 2011 Jul 22.
L-DOPA remains the most effective treatment for Parkinson's disease (PD). However, long-term administration of L-DOPA is compromised by complications, particularly dyskinesia. Serotonergic type 1A (5-HT(1A)) receptor agonists and serotonergic type 2A (5-HT(2A)) receptor antagonists were, until recently, considered to be promising therapies against dyskinesia. However, there have been some recent high-profile failures in clinical trials, notably with sarizotan, and it seems that these classes of drugs may also impair l-DOPA antiparkinsonian efficacy. A simple explanation for the loss of antiparkinsonian benefit might be lack of good selectivity of these compounds for their respective targets, particularly with respect to off-target actions on dopaminergic receptors or poor dose selection in clinical studies. However, such explanations do not hold broadly when considering the actions of all compounds studied to date, whether in animal models or clinical trials. Here, we review 5-HT(1A) and 5-HT(2A) receptor function in PD and provide an anatomically based rationale as to why in some instances 5-HT(1A)- and 5-HT(2A)-modulating drugs might worsen parkinsonism, in addition to reducing dyskinesia. We propose that, in addition to selectivity for specific receptor subtypes, to target 5-HT(1A) and 5-HT(2A) receptors to alleviate dyskinesia, without worsening parkinsonism, it will be necessary to develop compounds that display anatomical selectivity, targeting corticostriatal transmission, while avoiding 5-HT receptors on ascending serotonergic and dopaminergic inputs from the raphe and substantia nigra, respectively.
左旋多巴仍然是治疗帕金森病（PD）最有效的方法。然而，长期服用左旋多巴会导致并发症，尤其是运动障碍。直到最近，5-羟色胺 1A 型（5-HT（1A））受体激动剂和 5-羟色胺 2A 型（5-HT（2A））受体拮抗剂被认为是对抗运动障碍的有前途的治疗方法。然而，最近一些临床试验出现了一些引人注目的失败，特别是 sarizotan，似乎这些类药物也会损害 l-DOPA 抗帕金森病的疗效。抗帕金森病益处丧失的一个简单解释可能是这些化合物对其各自靶标的选择性不足，特别是在针对多巴胺能受体的脱靶作用或在临床研究中选择不当的剂量方面。然而，当考虑迄今为止所有研究的化合物的作用时，这种解释并不普遍，无论是在动物模型还是临床试验中。在这里，我们回顾了 5-HT（1A）和 5-HT（2A）受体在 PD 中的作用，并提供了一个基于解剖学的基本原理，说明为什么在某些情况下，5-HT（1A）和 5-HT（2A）调节药物可能会加重帕金森病，除了减少运动障碍。我们提出，除了对特定受体亚型的选择性外，为了靶向 5-HT（1A）和 5-HT（2A）受体来缓解运动障碍，而不加重帕金森病，有必要开发显示解剖选择性的化合物，靶向皮质纹状体传递，同时避免来自中缝核和黑质的上行 5-羟色胺能和多巴胺能输入的 5-HT 受体。
