Preclinical studies have emphasized that persistent small afferent input will induce a state of central facilitation, which can be regulated by systemically administered sodium channel blockers. We have extended these preclinical studies to the human volunteers by examining the effects of lamotrigine and 4030W92, two structurally related voltage-sensitive sodium channel antagonists, on acute sensory thresholds and facilitated processing induced by intradermal capsaicin. Fifteen healthy subjects received 4030W92, lamotrigine, and placebo in a randomized order using double-blinded crossover design methodology in three sessions each separated by a 7-day washout period. In each session, baseline neurosensory testing was performed on the volar aspect of the subject's left forearm. Subjects were then dosed with either lamotrigine (300 mg), 4030W92 (100 mg), or placebo, followed 2 h later by capsaicin (100 microg) injected intradermally on the volar aspect of the left forearm. Pain scores, blood pressure, heart rate, and respiratory rate were measured at the time of injection and every 5 min for 15 min. Fifteen minutes after the capsaicin injection, the hyperalgesic area was determined by von Frey hair, stroking, and heat; the flare response was outlined; and neurosensory testing again was performed halfway between the edge of the hyperalgesic area and the capsaicin injection site. While capsaicin significantly decreased the hot pain and VF pain thresholds, oral lamotrigine and 4030W92 failed to alter this response to capsaicin, relative to placebo treatment. Similarly, oral lamotrigine or 4030W92 did not alter the pain scores reported from mechanical pain stimuli at any time postcapsaicin. This study showed a lack of effect of two structurally similar sodium channel antagonists on a human experimental pain model using intradermal capsaicin, which is consistent with other studies on the effects of sodium channel antagonists of capsaicin-induced pain and hyperalgesia. This lack of effect stands in contrast to reported effects of sodium channel antagonists on preclinical models of cutaneous hyperalgesia or effects of lamotrigine on clinical neuropathic pain.

2003-03-01·Neuropharmacology2区 · 医学

Differential interactions of lamotrigine and related drugs with transmembrane segment IVS6 of voltage-gated sodium channels

2区 · 医学

Article

作者: G. Liu ; J. J. Clare ; W. A. Catterall ; T. Scheuer ; M. Nobbs ; Vladimir Yarov-Yarovoy

Voltage-gated sodium channels are blocked by local anesthetic and anticonvulsant drugs. A receptor site for local anesthetics has been defined in transmembrane segment S6 in domain IV (IVS6) of the alpha subunit, but the anticonvulsant lamotrigine and related compounds have more complex structures than local anesthetics and may interact with additional amino acid residues. Apparent K(D) values for inactivated-state block of rat brain type IIA sodium channels expressed in Xenopus oocytes were 31.9 micro M, 17.3 micro M, 3.7 micro M and 10.3 micro M for lamotrigine and compounds 227c89, 4030w92 and 619c89, respectively. Compound 619c89 was the strongest frequency-dependent blocker, which correlated with higher affinity and a five-fold slower recovery from drug block compared to lamotrigine. Examination of lamotrigine block of mutant sodium channel alpha subunits, in which alanine had been substituted for each individual amino acid in IVS6, identified mutations I1760A, F1764A and Y1771A as causing the largest reductions in affinity (six-, seven- and 12-fold, respectively). The ratios of effects of these three mutations differed for compounds 227c89, 4030w92, and 619c89. The amino acid residues interacting with these pore-blocking drugs define a surface of IVS6 that is exposed to the pore and may rotate during gating.

2002-06-01·The journal of pain2区 · 医学

A multicenter, double-blind, randomized, placebo-controlled crossover evaluation of a short course of 4030W92 in patients with chronic neuropathic pain

2区 · 医学

Article

作者: Troels S. Jensen ; Gary J. Bennett ; Steve Quessy ; Mark S. Wallace ; Rosemarie Pladna ; Michael Rowbotham

Several lines of evidence suggest that neuropathic pain is mediated in part by an increase in the density of voltage-sensitive sodium channels in injured axons and the dorsal root ganglion of injured axons. The purpose of this study was to examine the safety, analgesic efficacy, and tolerability of oral 4030W92 (a new novel sodium channel blocker) in a group of subjects with chronic neuropathic pain. This study used a randomized, double-blind, placebo-controlled, crossover design in 41 subjects with neuropathic pain with a prominent allodynia. Each subject received a 2-week course of 4030W92 (25 mg/day) and placebo separated by a 2-week washout period. At baseline, postdose day 1, day 7, and day 14, the following were measured: (1) spontaneous and evoked pain scores, (2) dynamic and static allodynia mapping, (3) Short Form McGill Pain Questionnaire, and (4) blood sample for 4030W92 assay. At baseline and day 14 the following were measured: (1) thermal testing in the painful area, (2) Medical Outcomes Study Short Form 36 Questionnaire, and (3) patient global satisfaction. Allodynia severity was significantly lower (P = .046) on treatment day 1, postdose for 4030W92 compared to placebo. However, this was not maintained on treatment day 7 or 14. The area of static allodynia was significantly smaller (P = .03) on treatment day 7 for 4030W92 compared to placebo. However, this was not maintained to treatment day 14. There was no significant effect of 4030W92 on any other efficacy measure. Side effects were minimal. 4030W92, at 25 mg/day, produced a nonsignificant reduction in pain without treatment limiting side effects. The maximum analgesic effect of this drug remains unknown.

项与 4030W92 相关的新闻（医药）

2023-10-09

·生物谷

以Nav通道为靶点的药理学研究已证明其在治疗多种疾病方面具有巨大价值，开发以Nav通道为靶点的新药是药物化学研究的一个活跃领域。该领域药物开发的一个特殊挑战是精确地靶向Nav通道的特定亚型或状态，以尽颜宁教授团队在《美国国家科学院院刊》（PNAS）发表了题为：Dual-pocket inhibition of Nav channels by the antiepileptic drug lamotrigine 的研究论文。该研究揭示了揭示了两种临床药物拉莫三嗪（LTG，用于癫痫和双相情感障碍治疗）和利鲁唑（RLZ，用于渐冻症治疗）靶向并阻断Nav1.7的不同机制，利鲁唑直接与结合于Nav1.7的α亚基的孔结构域（pore domain，PD）的中央腔来阻断Nav1.7，而拉莫三嗪通过双口袋机制阻断Nav1.7，一个LTG分子同样结合到中央腔，另一个LTG分子结合到BIG位点。该研究揭示了这些药物作用机制的分子基础，将有助于开发新的抗癫痫药物和止痛药物。颜宁教授表示，万万没想到，在具有不同化学骨架的不同类型的Nav靶向化合物中，竟然都具有双口袋抑制模式，例如拉莫三嗪（LTG）、拉考沙胺（LCM，一种抗癫痫药物）和大麻二酚（CBD，一种止痛抗炎药物）。这些发现不仅解释了各种临床和研究药物不同作用机制的分子基础，而且为基于结构的理性设计下一代更具疗效和选择性的抗癫痫药物和非成瘾性止痛药物建立了框架。 Nav通道对肌肉收缩、感觉知觉和神经递质释放等多种生理过程至关重要，这些通道由一个成孔的α亚基（包括1个离子传导孔结构域和4个电压感应结构域）以及调节通道功能和定位的辅助β亚基组成。 Nav通道的功能障碍与多种心血管疾病和神经和精神疾病有关，例如癫痫、心律失常、神经性疼痛和自闭症等。因此，各种Nav抑制剂已被开发出来，并在临床上用作局部麻醉剂、抗癫痫药物、抗心律失常药物，以及止痛药。然而，这些药物通常是中等疗效，对不同的Nav亚型具有相对非选择性，从而导致不必要的副作用。近年来，Nav药理学已经转向开发新一代阻断剂，具有更好的疗效和亚型选择性。 Nav1.7是由SCN9A基因编码，主要定位于背根神经节神经元，被认为是疼痛治疗的重要靶点。Nav1.7的功能丧失会导致对疼痛不敏感，而在原发性红斑性肢痛症、阵发性剧痛症和小纤维神经病患者中，则发现了Nav活性增强突变。尽管许多卓越的制药公司付出了巨大努力，但大多数靶向Nav1.7的候选药物未能达到2期临床试验终点。Nav1.7与临床药物或先导化合物结合的复合物结构细节可能为我们提供分子水平的洞察力，这将有助于合理的药物设计和优化。拉莫三嗪（Lamotrigine，LTG），商品名为利必通（Lamictal），由葛兰素史克公司（GSK）开发，是FDA批准的用于癫痫和双相情感障碍一线治疗的药物。利鲁唑（Riluzole，RLZ），商品名为力如太（Rilutek），由赛诺菲公司（Sanofi）开发，是FDA批准的用于渐冻症（ALS）和其他运动神经元疾病的治疗药物。尽管已经对LTG和RLZ作为非选择性Nav阻断剂进行了广泛研究，但这两款药物与Nav通道的结合细节仍不清楚。 Nav通道的高分辨率结构与这些临床药物的复合物将提供深入了解其作用机制（MOA）的化学基础，并有助于开发下一代抗癫痫药物和止痛药。 2023年6月，颜宁团队在 Nature Communications 期刊发表论文【2】，其中绘制了Nav通道上药物结合位点的结构图。在这项发表于 PNAS 的最新研究中，研究团队采用存在β1和β2亚基的Nav1.7通道复合物作为支架，对代表性的Nav靶向药物的作用机制进行了冷冻电镜分析。解析了利鲁唑（RLZ）和拉莫三嗪（LTG）结合的人类Nav1.7的冷冻电镜结构，分辨率分别为2.9Å和2.7Å，还获得了无配体Nav1.7的3D电镜结构重建，分辨率为2.1Å。结果显示，利鲁唑（RLZ）直接结合于Nav1.7的α亚基的孔结构域（pore domain，PD）的中央腔，由重复序列III和IV的残基配位，从而直接阻断孔结构域。而拉莫三嗪（LTG）则通过双口袋机制阻断Nav1.7，一个LTG分子同样结合到中央腔，另一个LTG分子结合到BIG位点。因此，LTG与拉考沙胺（lacosamide，一种抗癫痫药物）和大麻二酚（cannabidiol，一种止痛抗炎药物）类似，通过双口袋机制阻断Nav通道。在过去几十年里，研究人员开发出了许多以拉莫三嗪（LTG）为基础骨架的LTG相关线性6,6系列化合物作为潜在的抗癫痫和止痛候选药物。对LTG的杂环核心和芳基取代模式的化学修饰，会提高对对Nav通道的疗效（例如BW-4030W92）和亚型特异性（PF-01247324）。该研究通过对结构解析，辅以对接和突变分析，解释了LTG相关线性6,6系列的结构活性关系，揭示了这些候选药物作用机制的分子基础，从而有助于开发新型抗癫痫药物和止痛药物。以Nav通道为靶点的药理学研究已证明其在治疗多种疾病方面具有巨大价值，开发以Nav通道为靶点的新药是药物化学研究的一个活跃领域。该领域药物开发的一个特殊挑战是精确地靶向Nav通道的特定亚型或状态，以尽量减少脱靶效应。但长期以来，由于缺乏精确的结构，阻碍了靶向Nav通道药物的合理设计。近年来Nav通道的结构研究蓬勃发展，但人工智能（AI）促进的药物发现仍然受到训练数据库有限的限制，其中配体结合结构的数量仍然很少。此外，构象动力学超出了目前结构预测的能力，因此，与配体结合的靶蛋白的实验结构解析对于药物发现是必不可少的。颜宁团队通过阐明与原型药物结合的各种人类Nav通道的高分辨率结构来应对这一挑战。这项研究不仅解释了各种临床和研究药物不同作用机制的分子基础，而且为基于结构的理性设计下一代更具疗效和选择性的抗癫痫药物和非成瘾性止痛药物建立了框架。