Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects.
Characterization of novel cannabinoid based T-type calcium channel blockers with analgesic effects.
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DOI：
10.1021/cn500206a
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发表时间：
2015-02-18
影响因子：
5
通讯作者：
Zamponi, Gerald W.
中科院分区：
文献类型：
--
作者：
Bladen, Chris;McDaniel, Steven W.;Gadotti, Vinicius M.;Petrov, Ravil R.;Berger, N. Daniel;Diaz, Philippe;Zamponi, Gerald W.
关键词：
低电压激活的(T型)钙通道是初级传入通路中传递伤害性信息的重要调节器，寻找调节这些通道的配体是药物发现领域的一个关键焦点。最近，我们鉴定了一组具有混合大麻素受体/T型通道阻断活性的新化合物，并在动物疼痛模型上检测了它们的镇痛作用。在这里，我们在之前这些发现的基础上，合成了一系列新的小分子有机化合物。然后，我们使用全细胞电压钳技术对它们进行筛选，以确定最有效的T型钙通道抑制剂。两个最有效的阻滞剂(化合物9和10)随后通过放射配基结合分析来确定它们与CB1和CB2受体的亲和力。通过构效关系和优化研究，发现了一种新的T型钙通道阻滞剂化合物9。化合物9对小鼠急性炎症性疼痛模型有镇痛作用，对部分神经结扎模型有减轻触觉过敏的作用。该化合物在治疗相关浓度下对Cav3.2T型钙通道缺失小鼠无效，并且在旷场测试中没有引起明显的运动障碍。综上所述，我们的数据揭示了一类新的化合物，其生理和治疗作用是通过阻断Cav3.2钙通道介导的。
Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure–activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels.
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