Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana, United States.
Indiana University/Purdue University, Riley Hospital, Indianapolis, Indiana, United States.
CNS Neurol Disord Drug Targets. 2017;16(10):1099-1110. doi: 10.2174/1871527316666171101132047.
BACKGROUND & OBJECTIVE: 6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]- 3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8 that is under development for epilepsy. The present study provided a broad inquiry into its anticonvulsant properties. LY3130481 was anticonvulsant in multiple acute seizure provocation models in mice and rats. In addition, LY3130481 was effective against absence seizures in the GAERS genetic model and in the Frings mouse model. Likewise, LY3130481 attenuated convulsions in mice and rats with long-term induction of seizures (e.g., corneal, pentylenetetrazole, hippocampal, and amygdala kindled seizures). In slices of epileptic human cortex, LY3130481 significantly decreased neuronal firing frequencies. LY3130481 displaced from rat brain a radioligand specific for AMPA receptors associated with TARP γ-8 whereas non-TARP-selective molecules did not. Binding was also observed in hippocampus freshly transected from a patient.
RESULTS & CONCLUSION: Taken as a whole, the findings reported here establish the broad anticonvulsant efficacy of LY3130481 indicating that blockade of AMPA receptors associated with TARP γ-8 is sufficient for these protective effects.
6-[(1S)-1-[1-[5-(2-羟乙氧基)-2-吡啶基]吡唑-3-基]乙基]-3H-1,3-苯并噻唑-2-酮（LY3130481 或 CERC-611）是一种 AMPA 受体选择性拮抗剂，其含有跨膜 AMPA 受体调节蛋白（TARP）γ-8，目前正在开发用于治疗癫痫。本研究对其抗惊厥特性进行了广泛研究。LY3130481 在多种急性惊厥诱发模型中对小鼠和大鼠具有抗惊厥作用。此外，LY3130481 在 GAERS 遗传模型和 Frings 小鼠模型中对失神发作有效。同样，LY3130481 可减轻具有长期诱导发作的小鼠和大鼠的惊厥（例如角膜、戊四氮、海马和杏仁核点燃发作）。在癫痫患者皮质的切片中，LY3130481 显著降低神经元的放电频率。LY3130481 从大鼠脑中置换出与 TARP γ-8 相关的 AMPA 受体的放射性配体，而非 TARP 选择性分子则不能。在从患者新鲜横切的海马体中也观察到结合。
总的来说，这里报道的发现确立了 LY3130481 的广泛抗惊厥疗效，表明与 TARP γ-8 相关的 AMPA 受体的阻断足以产生这些保护作用。
