Anxiolytic effects of maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels
Anxiolytic effects of maxipost (BMS-204352) and retigabine via activation of neuronal Kv7 channels
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DOI：
10.1124/jpet.105.083923
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发表时间：
2005-07-01
影响因子：
3.5
通讯作者：
Mirza, NR
中科院分区：
文献类型：
--
作者：
Korsgaard, MPG;Hartz, BP;Mirza, NR
神经元K(v)7通道被认为是治疗高兴奋性疾病（如疼痛、癫痫和躁狂）的潜在药物靶点。杏仁核的过度活跃已经在焦虑的临床和临床前研究中被描述，因此，神经元K(v)7通道可能是这一适应症的相关靶点。在表达K(v)7通道亚型的细胞系的膜片钳电生理实验中，Maxipost （BMS-204352）对所有神经元K(v)7通道发挥正调节作用，而其r -对构象则是负调节作用。相比之下，在K(v)7.1和大电导Ca2+活化的钾离子通道上，两种对映体表现出相同的作用，即在两个通道上分别发生负调制和正调制。在非洲爪蟾卵母细胞中表达的GABA(A)受体(α (1) β (2) γ (2s)和α (2) β (2) γ (2s))中，BMS-204352为负调剂，r -对映体为正调剂。观察到S-和r -形式对神经元K(v)7通道亚型表现出相反的作用，这使我们能够评估K(v)7通道在焦虑中的潜在作用。在体内，BMS-204352 （3 ~ 30 mg/kg）对小鼠零迷宫和大理石埋地焦虑模型具有抗焦虑作用，对埋地模型有拮抗作用（3 mg/kg）。同样，阳性K(v)7通道调节剂瑞加宾在两种模型中都具有抗焦虑作用，其在掩埋模型中的作用被K(v)7通道抑制剂10,10-双吡啶-4-甲基- 10h -蒽-9-one (xie -991) （1 mg/kg）阻断。BMS-204352和瑞gabine诱导焦虑缓解的剂量可能与镇静或记忆损伤的作用分离。总之，这些体外和体内研究提供了令人信服的证据，证明神经元kv7通道是开发新型抗焦虑药的靶点。
Neuronal K(v)7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal K(v)7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing K(v)7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal K(v)7 channels, whereas its R-enantiomer was a negative modulator. By contrast, at the K(v)7.1 and the large conductance Ca2+-activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA(A) receptors (alpha(1)beta(2)gamma(2s) and alpha(2)beta(2)gamma(2s)) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S- and R-forms exhibited opposing effects on neuronal K(v)7 channel subtypes allowed us to assess the potential role of K(v)7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive K(v)7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the K v 7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal K v 7 channels are a target for developing novel anxiolytics.