Agonists and antagonists induce different palonosetron dissociation rates in 5-HT(3)A and 5-HT(3)AB receptors

作者：Lummis Sarah C R^*; Thompson Andrew J

来源：Neuropharmacology, 2013, 73: 241-246.

DOI：10.1016/j.neuropharm.2013.05.010

• Serotonin receptor
• Allosteric binding site
• Site-directed mutagenesis
• Radioligand binding
• FlexStation assays

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-HT(3)A and 5-HT(3)AB receptors. We used receptors expressed in HEK293 cells, and functionally analysed them using a membrane potential sensitive dye in a Flexstation, which revealed IC(50)s of 0.24 nM and 0.18 nM for 5-HT(3)A and 5-HT(3)AB receptors respectively. Radioligand binding studies with [H-3]palonosetron revealed similar K(d)s: 0.34 nM for 5-HT(3)A and 0.15 nM for 5-HT(3)AB receptors. Kinetic studies showed palonosetron association and dissociation rates were slightly faster in 5-HT(3)AB than 5-HT(3)A 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 [H-3]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 (t(1/2) > 10 h) could at least partly explain the long duration of palonosetron effects in vivo.

• 出版日期2013-10