5-羟色胺3受体拮抗剂YM060、YM114（KAE-393）、格拉司琼和昂丹司琼对大鼠迷走神经和大脑皮层亲和力的比较研究。

Comparative study of the affinities of the 5-HT3 receptor antagonists, YM060, YM114 (KAE-393), granisetron and ondansetron in rat vagus nerve and cerebral cortex.

作者信息

Ito H, Akuzawa S, Tsutsumi R, Kiso T, Kamato T, Nishida A, Yamano M, Miyata K

机构信息

Neuroscience and Gastrointestinal Research Laboratory, Yamanouchi Pharmaceutical Co. Ltd., Ibaraki, Japan.

出版信息

Neuropharmacology. 1995 Jun;34(6):631-7. doi: 10.1016/0028-3908(95)00033-3.

DOI:10.1016/0028-3908(95)00033-3

PMID:7566499

Abstract

The 5-HT3 receptor blocking properties of YM060, YM114 (KAE-393), granisetron and ondansetron were examined in the vagus nerve and cerebral cortex of rats. 5-HT and 2-methyl-5-HT induced dose-dependent depolarizations of rat isolated vagus nerve with EC50 values of 2.53 (1.93-3.33) x 10(-6) and 4.03 (2.87-5.66) x 10(-6) M, respectively. YM060, YM114 and granisetron dose-dependently antagonized the depolarization of the rat vagus nerve induced by 5-HT, with decreases in the slope and maximal response at higher concentrations. Apparent pA2 values for these antagonists were 10.27 +/- 0.09, 10.12 +/- 0.16 and 9.44 +/- 0.40, respectively. Ondansetron produced a clear rightward shift of the concentration-response curve to 5-HT. The pA2 value was 8.63 (8.23-9.68). YM060 and YM114 at up to 10(-5) M produced no significant depression of the depolarizing responses to DMPP and GABA. YM060, YM114, granisetron and ondansetron displaced specific binding of [3H]GR65630 to rat cortical membranes with pKi values of 10.48 (10.41-10.57), 10.24 (10.18-10.28), 9.15 (9.02-9.28) and 8.70 (8.64-8.77), respectively. An excellent correlation (r = 0.97) was obtained between pA2 values in the vagus nerve and pKi values in the cerebral cortex. YM060, YM114, granisetron and ondansetron showed low affinities for 5-HT1A, 5-HT2 receptor, adrenergic alpha 1, alpha 2, dopamine D2, muscarinic M2, mu-opioid, benzodiazepine and histamine H1 receptors. These results support the possibility that the same type of 5-HT3 receptor occurs in rat vagus nerve and cerebral cortex.

摘要

在大鼠的迷走神经和大脑皮层中检测了YM060、YM114（KAE-393）、格拉司琼和昂丹司琼的5-羟色胺3（5-HT3）受体阻断特性。5-羟色胺（5-HT）和2-甲基-5-羟色胺（2-methyl-5-HT）可诱导大鼠离体迷走神经产生剂量依赖性去极化，其半数有效浓度（EC50）值分别为2.53（1.93 - 3.33）×10⁻⁶和4.03（2.87 - 5.66）×10⁻⁶ M。YM060、YM114和格拉司琼可剂量依赖性地拮抗由5-HT诱导的大鼠迷走神经去极化，在较高浓度时斜率和最大反应降低。这些拮抗剂的表观亲和力指数（pA2）值分别为10.27±0.09、10.12±0.16和9.44±0.40。昂丹司琼使5-HT的浓度-反应曲线明显右移。pA2值为8.63（8.23 - 9.68）。高达10⁻⁵ M的YM060和YM114对二甲基苯基哌嗪（DMPP）和γ-氨基丁酸（GABA）的去极化反应无明显抑制作用。YM060、YM114、格拉司琼和昂丹司琼可取代[³H]GR65630与大鼠皮层膜的特异性结合，其抑制常数（pKi）值分别为10.48（10.41 - 10.57）、10.24（10.18 - 10.28）、9.15（9.02 - 9.28）和8.70（8.64 - 8.77）。迷走神经中的pA2值与大脑皮层中的pKi值之间具有良好的相关性（r = 0.97）。YM060、YM114、格拉司琼和昂丹司琼对5-羟色胺1A（5-HT1A）、5-羟色胺2受体、肾上腺素能α1、α2、多巴胺D2、毒蕈碱M2、μ-阿片样物质、苯二氮䓬和组胺H1受体的亲和力较低。这些结果支持大鼠迷走神经和大脑皮层中存在同一类型5-HT3受体的可能性。