Epilepsy and sodium channel blockers

Epilepsy is one of the most frequent neurological diseases and although most patients nowadays respond well to anti-epileptic drugs (AED), 30 - 40% of them still present seizures despite treatment with 2 or more AED. This illustrates the need for discovery and testing of new molecules designed for specific brain targets. Several voltage-gated Na⁺ channel gene mutations were shown to be associated with genetic and hereditary epilepsy. Thus, while it is noteworthy that some currently available AED act through Na⁺ channels, the identified mutations in Na⁺ channel genes strongly support the development of new Na⁺ channel blockers used as AED. This review focuses on the pathophysiology of epilepsy and particularly on insight gained from the identification of mutations in idiopathic epilepsy (IE). All of the IE mutations identified concern genes coding for ion channels, suggesting a possible role of these integral membrane proteins in epileptogenesis. The recent identification of mutations in genes encoding the α1, α2 and β1 subunits of the voltage-gated Na⁺ channel (SCN1A, SCN2A, SCN1B) and their association with febrile seizures (FS) further illustrates the contribution of these channels in epilepsy. Modes of action of AED supposed to act through the voltage-gated Na⁺ channels are examined in an attempt to propose alternative routes to discover new active compounds.     

Recent patents on calcium channel blockers: emphasis on CNS diseases

Introduction: Altered homeostasis of cell calcium movement is a central stage in multiple diseases of CNS. This explains the great therapeutic interest in blockers for the various subtypes of voltage-activated calcium channels (VACCs) expressed in neurons. Mitigation of Ca²⁺ entry excess elicited by those blockers may restore the altered synaptic transmission, synaptic plasticity and gene expression to normal parameters, ending the enhanced neuronal vulnerability.

Areas covered: This review summarize 23 patents on ligands for L-, N- or T-type channels, claimed to have potential therapeutic interest in epilepsy, pain, migraine and neurodegenerative diseases.

Expert opinion: Collections of compounds are generally screened in cell lines expressing a given subtype of VACCs. IC₅₀ to block such channels are often, but not always, provided. In few instances, compounds exhibiting the highest potency in in vitro experiments are also tested in animal models of pain, behavior, epilepsy or Alzheimer’s disease. Attempts to develop selectivity for a given VACC subtype with non-peptidic organic ligands have so far failed. Due to their wide tissue expression, such selectivity is crucial for minimizing possible side effects. However, the few data reported by patents does not allow prediction of selectivity of the new compounds in many cases.     

氯通道阻断剂和白头翁皂苷的协同溶血作用

目的研究氯通道阻断剂对白头翁皂苷溶血的影响。方法用细胞图像软件记录并分析白头翁皂苷的溶血过程,检测红细胞溶血率,并观察氯通道阻断剂对白头翁皂苷溶血的影响。结果白头翁皂苷药物引起人红细胞溶血,溶血作用呈浓度依赖性,在0.5～2 mmol.L-1范围内,随药物浓度增高,溶血率越高,且红细胞发生溶血所需时间越短。氯通道阻断剂NPPB、tamoxifen可以促进白头翁皂苷的溶血作用,与单用白头翁皂苷组比较,在相同作用时间条件下,联合应用白头翁皂苷与氯通道阻断剂(NPPB、tamoxifen)时,溶血率明显提高,且发生红细胞全部溶血所需的时间明显缩短。结论白头翁皂苷溶血作用呈浓度依赖性,氯通道阻断剂与白头翁皂苷有协同溶血作用。     

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca²⁺ channel current (I_Ca) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K⁺ channel currents (I_Kr, I_Ks) and voltage-gated Na⁺ channel current (I_Na). The concentration-dependent inhibition of Ca²⁺ channel currents (I_Ca) was examined in rat cardiomyocytes; these CCBs have similar potency on I_Ca channel blocking with IC₅₀ (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD₅₀ and APD₉₀ already at 1 µM whereas NIC and AML shortened APD₅₀ but not APD₉₀ up to 30 µM. According to ion channel studies, NIC and AML concentration-dependently inhibited I_Kr and I_Ks while ISR had only partial inhibitory effects (<50% at 30 µM). Inhibition of I_Na was similarly observed in the three CCBs. Since the I_Kr and I_Ks mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of I_Ca.     

神经元上的小电导钙激活钾通道的研究进展

小电导的钙激活钾通道 (SK)具有K+ 选择性 ,Ca2 + 高敏性和电压不依赖等特性 ,广泛分布在神经元上。参与产生慢后超级化电位 ,通过放电频率适应影响神经元的放电功能。SK通道主要包括SK1,SK2 ,SK3 3种通道 ,通道活性受Ca2 + ,钙调蛋白 (CaM )以及一些神经递质的调节。SK通道的改变可能与学习记忆失调 ,精神分裂症以及神经肌肉失调等疾病有关     

Sodium channel blockers for neuropathic pain

Importance of the field: The voltage-gated sodium channels (VGSCs) play a fundamental role in controlling cellular excitability and their abnormal activity is related to several pathological processes, including cardiac arrhythmias, epilepsy, neurodegenerative diseases, spasticity, chronic and neuropathic pain. In particular, neuropathic pain (e.g., postherpetic and trigeminal neuralgia, diabetic neuropathy and spinal cord injury) is a serious clinical problem that affects a high percentage of the world population. Because an altered sodium channel isoform expression profile has been considered one reason for the changes in neuronal excitability, there is a continuous quest for new selective molecules targeting sodium channels for the treatment of chronic pain.

Areas covered in this review: PubMed, http://www.sciencedirect.com/, SciFinder^® Scholar and http://ep.espacenet.com/ were used as sources for this review and patents between 2007 and September 2009 were taken into account for the sodium channel blockers molecular classes reviewed and discussed herein.

What the reader will gain: The sodium channel blockers reported in this review have been categorized into different molecular classes on the basis of their wide structural diversity. This classification, somewhat arbitrary, does not necessarily reflect the presence of pharmacophoric elements but offers a useful way to discuss and comment on structurally homogenous classes of chemotypes recently patented.

Take home message: The continuous discoveries in the field of sodium channel blockers, highlighted by the increasing numbers of patent applications published in the last few years and by the numbers of compounds currently in clinical development, underline the importance of this target for the treatment of neuropathic pain. The great difficulty in the design of new selective and active structures, not obtained from old VGSC blockers that are often associated with high risk of adverse effects, is a strong challenge for medicinal chemistry research.     

ATP敏感性钾通道的阻断剂与开放剂研究进展

ATP敏感性钾通道是高血压、心绞痛、糖尿病及缺血性脑损伤等多种疾病的治疗靶点之一。通过对调节KATP通道药物的选择性、可逆性、作用位点以及相互调节的研究，可以对一些临床用药进行重新评估，并指导开发高选择性的KATP通道阻断剂和开放剂。     

Analgesic actions of the N-type voltage-dependent calcium channel blockers

OBJECTIVE The participation of N-type voltage-dependence calcium channel(N-VDCC) in pain transmission has been proved,and the analgesia of N-VDCC blokcers has also been confirmed.The aim of this study was to obtain the small molecular N-VDCC blockers with oral analgesic activity and tho investigate the characteristics of its analgesia.METHODS Taken NMED-160 and ZC88 as leading compounds,a series of candidates of non-peptide N-VDCC blockers were synthesized.The inhibition of these chemicals to N-VDCC currents was tseted by using two-electrode voltage-clamp technique,and the oral analgesic activity was detected by using the model of chronic construction injury of sciatic nerve(CCI) in rats,a classic model of neuropathic pain.Among these compounds,D304 was selected to further investigate its analgesic action by using a variety of acute and chronic pain models.RESULTS Among these compounds we synthesized,eight compounds displayed high activity of inhibiting N-VDCC currents,and D214 and D304,showed strong oral analgesic activity in the rat CCI model.According to these results,D304 was selected to further study its analgesic action.In the mouse 55℃ hot-plate model,D304 given by oral route(10,30,100 mg·kg-1) failed to observed significant analgesia,suggesting that D304 had no effect on the thermal-stimulated acute pain.In the rat formalin-induced persistent pain model,D304 administered orally(10,30,100 mg·kg-1) dose-dependently inhibited formalin-induced pain in phaseⅡ,rather than in phaseⅠ,with equivalent intensity of analgesia to positive control of NMED-160.In the rat complete Freund adjuvant-induced chronic inflammatory pain model,D304(10,30,100 mg·kg-1,po) dose-dependently inhibited mechanical-stimulated allodynia and thermal-stimulated hyperalgesia,and its analgesic strength was equal to or even slightly stronger than that of NMED-160.In the two classical peripheral neuropathic pain models-the rat CCI model and the rat diabetic peripheral neuropathic pain model,D304(10,30,100 mg·kg-1,po) dose-dependently inhibited mechanical-stimulated allodynia and thermal-stimulated hyperalgesia,and its analgesic strength was slightly stronger than that of NMED-160 or gabapentin.The preliminary safety evaluation showed that the LD50 of D304(po) was 570 mg·kg-1,and therapeutic index was about 10.CONCLUSIONTaken together,we designed and synthesized a series of samll molecular N-VDCC blockers with oral analgesic activity.Among these compounds,D304 had no significant analgesia to acute pain,but showed strong oral analgesic activity to persistent and chronic pain,especially to chronic inflammatory pain and neuropathic pain.This findings set up a foundation for the further research and development of samll molecular N-VDCC blockers with oral analgesic activity.     

氯通道阻断剂对KCl、5-HT引起的兔脑椎基底动脉血管环收缩效应的影响

目的　探讨不同种类氯通道阻断剂在不同激动剂引起的脑血管平滑肌收缩反应中的作用。方法　记录离体兔脑椎基底动脉环收缩反应。结果　①氯通道阻断剂DIDS、Furosemide及NPPB均浓度依赖性抑制高K+ 及 5 HT引起血管环收缩反应 ,DIDS、Furosemide及NPPB对 5 HT引起收缩的抑制作用明显强于对KCl的作用 ;②在 5 HT引起血管收缩反应中 ,给予SK&F96 36 5引起血管最大舒张的基础上 ,DIDS、Furosemide及NPPB均可引起血管进一步舒张。结论　氯通道可能参与了由高K+ 去极化和 5 HT引起的兔脑椎基底动脉环收缩反应     

Human T-cell Kv1.3 potassium channel blockers: new strategies for immunosuppression

Blockers of the Kv1.3 channel, a voltage-gated K⁺ channel found in human T-cells, have recently been recognised as a general strategy for immunosuppression. These blockers are divided into two classes – peptidyl and non-peptidyl Kv1.3 channel blockers. This article covers the patents filed for Kv1.3 channel blockers dating from 1996 to the first quarter of 2000.     

作用于钾离子通道的抗心律失常药物的研发实例

鉴于心律失常病因的复杂性, 如何通过药物安全有效地控制心律失常疾病一直是亟待攻克的医药学难题。本文介绍了作用于钾离子通道的抗心律失常药物的研发实例, 并对抗心律失常药物的研究现状进行了综述和展望。     

钙通道阻滞剂对大鼠肝细胞钙释放激活的钙电流的影响(英文)

目的:研究钙通道拮抗剂对大鼠肝细胞钙释放激活的钙电流(I_(CRAC))的影响,方法:应用全细胞膜片箝技术。结果:I_(CRAC)的电流峰值是(-0.41±0.09)nA(n=15),反转电位约为0 mV,维拉帕米(Ver),地尔硫(艹卓)(Dil)和硝苯地平(Nif)显著降低I_(CRAC),不影响它的反转电位,Ver 5 μmol·L~(-1)的抑制率是40％±12％(n=3),Ver 50 μmol·L~(-1)使,CRAC的幅值从(-0.49±0.12)nA降到(-0.20±0.09)nA(n=5,P<0.01),抑制率为57％±15％,Dil和Nif 50 μmol·L~(-1)分别从(-0.43±0.10)nA(n=5),(-0.32±0.08)nA(n=5)降到(-0.29±0.07)nA(P<0.01),(-0.27±0.08)nA(P<0.01),抑制率分别为31％±11％,19％±7％,I_(CRAC)的幅值大小依赖细胞外钙浓度。I_(CRAC)在含台氏液1.8 mmol·L~(-1)中电流幅值为(-0.21±0.08)nA(n=3,P<0.01),结论:这三种钙通道拮抗剂有效抑制,I_(CRAC)并且通过抑制I~(CRAC)减少肝细胞钙超载。     

T型钙通道阻滞剂的临床应用进展

T型钙通道是一种低电压钙通道,在体内分布广泛,参与多种生理过程。T型钙通道阻滞剂是目前关注较多的一种新型钙通道阻滞剂,除具备与传统钙通道阻滞剂相似的降压作用外,还具有如降低心肌自律性、抗心肌重塑、保护肾功能、抗交感神经等药理作用。对T型钙通道阻滞剂的药理作用、药物相互作用与不良反应等研究进展进行综述,从而了解T型钙通道阻滞剂在临床实践中的应用现状,探索和开发其在临床实践中的新使用价值。     

Effect of potassium channel blockers on isolated rat atrium

This study describes a sensitive in vitro assay using isolated right atrium of adult Wistar rats to discover new compounds as K⁺ channel antagonists. For the purpose, several well-known K⁺ channel antagonists were investigated and compared with other compounds that modulate cardiac function. Potassium channel antagonists used in this study were barium chloride (BaCl₂), 4-aminopyridine (4-AP), tetraethylammonium (TEA), and E-4031. The concentration-dependent chronotropic and inotropic effect of K⁺ channel antagonists were determined under physiological condition and under depressed cardiac condition induced by stimulation of cholinergic M receptor with carbachol. Under physiological conditions, these K⁺ channel antagonists showed a negative chronotropic and positive inotropic response. When the spontaneous beat rate was decreased by cholinergic stimulation, these agents enhanced the beat rate and the force of contraction simultaneously. Study on new compounds found that agents S94052 and S94056 were similar to the above K⁺ channel antagonists in functional response. Current and voltage-clamp study demonstrated that both new compounds prolonged the duration of action potential and reduced the steady-state K⁺ outward currents. The functional study described here can provide a sensitive and reproducible atrium model to discover new K⁺ channel antagonists. Drug Dev. Res. 39:161–166. © 1997 Wiley-Liss, Inc.     

钙通道阻滞药与心肌顿抑

心肌顿抑是指短暂缺血后可逆性心肌收缩功能异常 ,是再灌注损伤的一种形式 ,临床上常出现该现象。钙通道阻滞药是心血管疾病常用药物 ,目前大量研究证明可以抑制心肌顿抑。本文综述了钙通道阻滞药治疗心肌顿抑的实验证据、理论基础以及在临床心肌顿抑中的应用等问题     

Calcium channel blockers: effect on morphine-induced hypermotility

Acute morphine treatment has been shown to cause a uniform calcium depletion in various brain regions and to evoke hypermotility in mice. On the other hand, it has been reported previously that calcium channel blockers reduce the behavioral stimulation induced by different methods in mice, and it is known that these drugs increase the morphine analgesia and reduce the abstinence syndrome. The effect of calcium channel blockers, nifedipine and diltiazem, on the morphine- and amphetamine-induced hypermotility were evaluated. Mice activity was measured with photocell motility meters. The results show that neither nifedipine nor diltiazem decrease significantly the motility in control and amphetamine-treated mice; however, when they were administered to morphine-treated mice the hypermotility was significantly reduced. The mechanism responsible for this interference is still unknown.     

Adrenalectomy potentiates the antinociceptive effects of calcium channel blockers

Calcium channel blockers can modulate the nociceptive threshold. However, the underlying mechanism(s), especially the role of hypothalamic-pituitary-adrenal (HPA) axis, on this effect has not yet been clarified. In the present study we investigated the analgesic effect of verapamil, diltiazem and nimodipine in intact and adrenalectomized (ADX) male rats and also measured the effect of these drugs on HPA function. The tail-flick and hot-plate tests were used to assess the nociceptive threshold before and 15, 30, 60 and 120 min after drug administration. Corticosterone level was measured by radioimmunoassay as a marker of HPA function. Our results showed that these drugs could elicit antinociceptive effects which were more prominent in the hot-plate than in the tail-flick tests. Following the exclusion of adrenal glands these drugs showed stronger analgesic effects. Acute administration of verapamil, diltiazem and nimodipine produced significant decrease in plasma corticosterone level that was more prominent by nimodipine. In conclusion, the results of our study show that the HPA function has an important role in the antinociceptive effect of calcium channel blockers.     

K+通道在Jurkat细胞调节性体积减小中的作用

目的：研究K^ 通道在Jurkat细胞调节性体积减小(RVD)中的作用。方法：调节细胞外不同离子浓度，用细胞成像系统测定Jurkat细胞(人T淋巴细胞肿瘤细胞株)在不同渗透压时细胞容积的变化。结果：细胞培养液中缺少Ca2^ ，或细胞培养液中的K^ 浓度升高，或使用Ca^2 敏感的K^ 通道(KCa)阻断剂均可抑制Jurkat细胞的RVD；应激免疫抑制蛋白(ISPS)具有抑制Jurkat细胞RVD的作用。结论：Jurkat细胞中KCa通道是RVD不可缺少的因素。ISPS对免疫功能抑制作用的机理之一，可能是抑制了T淋巴细胞上的K^ 通道。     

Efficacy of calcium channel blockers as maintenance therapy for asthma

AIMS: Previous bronchoprovocation studies indicate that nifedipine attenuates airway responsiveness to several stimuli whereas diltiazem has no effect. The aim of this study was to determine whether such studies predict the efficacy of calcium channel blockers as maintenance therapy for persistent asthma. METHODS: Twenty-one otherwise healthy adults with persistent asthma, mean age 25 years, completed treatment with maximum tolerated doses of placebo (P), nifedipine (N), and diltiazem (D) in a double-blind, randomized, three-treatment, three-period, crossover manner, each for 4 weeks. Frequency and severity of asthmatic symptoms were recorded twice daily, as well as peak expiratory flow and frequency of 'prn' use of inhaled terbutaline. Blood pressure, heart rate, P-R interval of the ECG and spirometry were measured biweekly. At the end of each treatment, airway responsiveness to exercise was measured. RESULTS: The mean (s.e. mean)% of days with wheeze was 69plus minus7% during P, 75plus minus6% during N and 72plus minus6% during D (P=0.7). FEV1 was 79plus minus2% of predicted during P, 81plus minus2% during N and 79plus minus2% during D (P=0.6). The decrease in FEV1 after exercise was 32plus minus4% during P, 32plus minus5% during N and 27plus minus4% during D (P=0.5). Heart rate was elevated during N (P=0.0002) whereas P-R interval was prolonged during D (P=0.0001). CONCLUSIONS: Maintenance therapy with calcium channel blockers, at doses that produce cardiovascular effects, do not suppress the signs and symptoms of persistent asthma. Previous bronchoprovocation studies did not predict these results.