Department of Biochemistry, University of Cambridge, Tennis Court Road, Cambridge CB2 1QW, UK.
Neuropharmacology. 2013 Oct;73:241-6. doi: 10.1016/j.neuropharm.2013.05.010. Epub 2013 Jun 5.
Palonosetron is a potent 5-HT₃ receptor antagonist with a unique structure and some unusual properties. Here we explore the properties of palonosetron at heterologously expressed 5-HT₃A and 5-HT₃AB receptors. We used receptors expressed in HEK293 cells, and functionally analysed them using a membrane potential sensitive dye in a Flexstation, which revealed IC₅₀s of 0.24 nM and 0.18 nM for 5-HT₃A and 5-HT₃AB receptors respectively. Radioligand binding studies with [(3)H]palonosetron revealed similar Kds: 0.34 nM for 5-HT3A and 0.15 nM for 5-HT₃AB receptors. Kinetic studies showed palonosetron association and dissociation rates were slightly faster in 5-HT₃AB than 5-HT₃A receptors, and for both subtypes dissociation rates were ligand-dependent, with antagonists causing more rapid dissociation than agonists. Similar ligand effects were not observed for [(3)H]granisetron dissociation studies. These data support previous studies which show palonosetron has actions distinct to other 5-HT3 receptor antagonists, and the slow rates observed for agonist induced dissociation (t₁/₂ > 10 h) could at least partly explain the long duration of palonosetron effects in vivo.
帕洛诺司琼是一种具有独特结构和一些不寻常特性的强效 5-HT₃受体拮抗剂。在这里，我们探索了帕洛诺司琼在异源表达的 5-HT₃A 和 5-HT₃AB 受体上的性质。我们使用在 HEK293 细胞中表达的受体，并使用 Flexstation 中的膜电位敏感染料对其进行功能分析，结果显示 5-HT₃A 和 5-HT₃AB 受体的 IC₅₀ 分别为 0.24 nM 和 0.18 nM。用 [(3)H]帕洛诺司琼进行放射性配体结合研究显示出相似的 Kd 值：5-HT3A 为 0.34 nM，5-HT₃AB 为 0.15 nM。动力学研究表明，帕洛诺司琼与 5-HT₃AB 受体的结合和解离速率比 5-HT₃A 受体略快，对于这两种亚型，解离速率均依赖于配体，拮抗剂比激动剂导致更快的解离。对于 [(3)H]granisetron 解离研究，没有观察到类似的配体效应。这些数据支持先前的研究，表明帕洛诺司琼的作用与其他 5-HT3 受体拮抗剂不同，并且观察到激动剂诱导的解离（t₁/₂ > 10 h）的缓慢速率至少部分解释了帕洛诺司琼在体内作用的持续时间长的原因。
