Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
Health Innovations Research Institute, RMIT University, Melbourne, VIC, Australia.
Br J Pharmacol. 2018 Jun;175(12):2284-2295. doi: 10.1111/bph.13910. Epub 2017 Jul 21.
Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Ca 2.2) and T-type (Ca 3.1, Ca 3.2 and Ca 3.3) voltage-gated calcium channels are particularly important in studying and treating pain and epilepsy.
In this study, whole-cell patch clamp electrophysiology was used to assess the potency and mechanism of action of a novel ortho-phenoxylanilide derivative, MONIRO-1, against a panel of voltage-gated calcium channels including Ca 1.2, Ca 1.3, Ca 2.1, Ca 2.2, Ca 2.3, Ca 3.1, Ca 3.2 and Ca 3.3.
MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCa 3.1, hCa 3.2 and hCa 3.3 (IC : 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCa 2.2 (IC : 34.0 ± 3.6 μM). It interacted with L-type calcium channels Ca 1.2 and Ca 1.3 with significantly lower potency (IC > 100 μM) and did not inhibit hCa 2.1 or hCa 2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCa 2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCa 3.1 channels suggesting a different mode of action between these two channels.
Selectivity, potency, reversibility and multi-modal effects distinguish MONIRO-1 from other low MW inhibitors acting on Ca channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCa 2.2 and hCa 3.1 channels. Such Ca channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies.
This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
电压门控钙通道参与中枢神经系统和外周神经系统的伤害感受。N 型（Ca 2.2）和 T 型（Ca 3.1、Ca 3.2 和 Ca 3.3）电压门控钙通道在研究和治疗疼痛和癫痫方面尤为重要。
在这项研究中，我们使用全细胞膜片钳电生理学方法评估了新型邻苯二甲酰亚胺衍生物 MONIRO-1 对包括 Ca 1.2、Ca 1.3、Ca 2.1、Ca 2.2、Ca 2.3、Ca 3.1、Ca 3.2 和 Ca 3.3 在内的一系列电压门控钙通道的效力和作用机制。
与 N 型钙通道 hCa 2.2（IC 50：34.0 ± 3.6 μM）相比，MONIRO-1 对人类 T 型钙通道 hCa 3.1、hCa 3.2 和 hCa 3.3 的抑制作用更强，效力高 5-20 倍（IC 50：分别为 3.3 ± 0.3、1.7 ± 0.1 和 7.2 ± 0.3 μM）。它与 L 型钙通道 Ca 1.2 和 Ca 1.3 的相互作用明显较弱（IC > 100 μM），并且在高达 100 μM 的浓度下不抑制 hCa 2.1 或 hCa 2.3 通道。观察到 hCa 2.2 通道的状态和使用依赖性抑制，而 hCa 3.1 通道在高刺激频率下发生更强的抑制，表明这两种通道之间存在不同的作用模式。
选择性、效力、可逆性和多模式作用将 MONIRO-1 与其他作用于参与疼痛和/或癫痫途径的钙通道的低 MW 抑制剂区分开来。高频放电增加了 MONIRO-1 对 hCa 2.2 和 hCa 3.1 通道的亲和力。这种钙通道调节剂在外周神经病性疼痛和其他伤害感受病理生理学的治疗中具有潜在的临床应用价值。
本文是关于靶向离子通道治疗慢性疼痛的最新进展的专题的一部分。要查看该部分中的其他文章，请访问 http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.
