THE EFFECT OF THE 5-HT3 RECEPTOR ANTAGONIST, RS-42358-197, IN ANIMAL-MODELS OF ANXIETY
THE EFFECT OF THE 5-HT3 RECEPTOR ANTAGONIST, RS-42358-197, IN ANIMAL-MODELS OF ANXIETY
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DOI：
10.1016/0014-2999(93)90710-y
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发表时间：
1993-03-30
影响因子：
5
通讯作者：
EGLEN, RM
中科院分区：
文献类型：
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作者：
COSTALL, B;DOMENEY, AM;EGLEN, RM
新型5-HT 3受体拮抗剂RS-42358的S-异构体（（S）-N-（1-氮杂双环[2.2.2]辛-3-基）-2，4，5，6-四氢-1-H-苯并[de]异喹啉-1-酮，RS-42358-197）可解除受光/暗试验箱厌恶情境抑制的小鼠的行为抑制。RS-42358-197在亚ng/kg剂量水平下有效，并且在1亿倍剂量范围内维持疗效。相反，R-异构体在所有研究剂量下均无效。S-异构体还可解除大鼠在社会交往和X-迷宫测试中的受抑制行为，并减少绒猴人类威胁测试中的焦虑相关行为。RS-42358-197可防止停止酒精、尼古丁、可卡因和地西泮给药后小鼠亮/暗试验中行为抑制的加重。因此，RS-42358的S-异构体在啮齿动物和灵长类动物模型中具有一致的非镇静抗焦虑作用。它是非常有效的，在高剂量下维持的功效使其作用与许多其他5-HT 3受体拮抗剂区分开来。
The S-isomer of the novel 5-HT3 receptor antagonist RS-42358 ((S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2,4,5,6-tetrahydro-1-H-benzo[de]isoquinolin-1-one, RS-42358-197) disinhibited behaviour in the mouse suppressed by the aversive situation of the light/dark test box. RS-42358-197 was effective at sub-ng/kg dose levels and the efficacy was maintained over a 100 million-fold dose range. In contrast, the R-isomer was ineffective at all doses studied. The S-isomer also disinhibited a suppressed behaviour in social interaction and elevated X-maze tests in the rat and reduced anxiety-related behaviours in a marmoset human threat test. RS-42358-197 prevented the exacerbation of the suppression of behaviour in the mouse light/dark test following withdrawal from treatment with alcohol, nicotine, cocaine and diazepam. Thus, the S-isomer of RS-42358 has a consistent non-sedating anxiolytic profile in rodent and primate models. It is exceptionally potent and a maintained efficacy at high doses distinguishes its actions from many other 5-HT3 receptor antagonists.