Kooyman A R, Zwart R, Vanderheijden P M, Van Hooft J A, Vijverberg H P
Research Institute of Toxicology, Utrecht University, The Netherlands.
Neuropharmacology. 1994 Mar-Apr;33(3-4):501-7. doi: 10.1016/0028-3908(94)90081-7.
Stereoselective effects of mianserin and ORG3770 on serotonin 5-HT3 receptors in mouse neuroblastoma N1E-115 cells have been investigated in radioligand binding and in whole-cell voltage clamp experiments. The specific binding of [3H]GR65630 to 5-HT3 recognition sites in N1E-115 cell homogenates is reduced by mianserin and ORG3770 and their enantiomers. The pKi values of the more potent (R)enantiomers of mianserin and ORG3770 are 8.44 and 8.62, respectively. The (R)enantiomers of mianserin and ORG3770 are 15 and 37 times more potent than their respective (S)enantiomers. The racemates are only 1.9 and 3.3 times less potent than the corresponding (R)enantiomers. In voltage clamp experiments the (R)enantiomers block the 5-hydroxytryptamine(5-HT)-induced ion current with pIC50 values of 8.52 for (R)mianserin and 8.26 for the (R)enantiomer of ORG3770. The (R)enantiomers of mianserin and ORG3770 are 24 and 145 times more potent in blocking the 5-HT-induced ion current than their respective (S)enantiomers. The racemates are 6 and 13 times less potent than the corresponding (R)enantiomers. In addition, the block of 5-HT-induced ion current by the (R)enantiomer of ORG3770 is partially reversed by a low concentration of its (S)enantiomer. The results indicate that the two enantiomers block the 5-HT3 receptor-mediated ion current in a mutually dependent manner.
在放射性配体结合实验和全细胞膜片钳实验中，研究了米安色林和ORG3770对小鼠神经母细胞瘤N1E-115细胞中5-羟色胺5-HT3受体的立体选择性作用。米安色林、ORG3770及其对映体可降低[3H]GR65630与N1E-115细胞匀浆中5-HT3识别位点的特异性结合。米安色林和ORG3770更有效的（R）对映体的pKi值分别为8.44和8.62。米安色林和ORG3770的（R）对映体的效力分别比其各自的（S）对映体强15倍和37倍。外消旋体的效力仅比相应的（R）对映体低1.9倍和3.3倍。在膜片钳实验中，（R）对映体阻断5-羟色胺（5-HT）诱导的离子电流，米安色林（R）的pIC50值为8.52，ORG3770（R）对映体的pIC50值为8.26。米安色林和ORG3770的（R）对映体在阻断5-HT诱导的离子电流方面比其各自的（S）对映体强24倍和145倍。外消旋体的效力比相应的（R）对映体低6倍和13倍。此外，低浓度的ORG3770（S）对映体可部分逆转ORG3770（R）对映体对5-HT诱导的离子电流的阻断作用。结果表明，两种对映体以相互依赖的方式阻断5-HT3受体介导的离子电流。
