Costall B, Domeney A M, Kelly M E, Tomkins D M, Naylor R J, Wong E H, Smith W L, Whiting R L, Eglen R M
Postgraduate Studies in Pharmacology, School of Pharmacology, University of Bradford, West Yorkshire, UK.
Eur J Pharmacol. 1993 Mar 30;234(1):91-9. doi: 10.1016/0014-2999(93)90710-y.
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.
新型5-HT3受体拮抗剂RS-42358（(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）的S-异构体可解除由明暗试验箱的厌恶情境所抑制的小鼠行为。RS-42358-197在亚纳克/千克剂量水平时有效，且在1亿倍的剂量范围内均保持有效性。相比之下，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交互动和高架十字迷宫试验中被抑制的行为，并在狨猴人类威胁试验中减少与焦虑相关的行为。RS-42358-197可防止小鼠在停止酒精、尼古丁、可卡因和地西泮治疗后明暗试验中行为抑制的加剧。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特性。它具有极高的效力，且在高剂量时仍保持有效性，这使其作用有别于许多其他5-HT3受体拮抗剂。
