Therapeutic Na+ channel blockers: Receptor & Drug Design

治疗性钠通道阻滞剂：受体

• 批准号: 6826554
• 负责人: GING K WANG
• 金额: $ 34.95万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6826554
• 关键词: amiodarone; amitriptyline; cell line; chemical structure function; chronic pain; drug adverse effect; drug design /synthesis /production; drug receptors; fentanyl; intermolecular interaction; ion channel blocker; laboratory rat; local anesthetics; mexiletine; nerve injury; neural transmission; nonhuman therapy evaluation; pimozide; receptor binding; sciatic nerve; sheep; site directed mutagenesis; sodium channel; tricyclic antidepressant; voltage /patch clamp

DESCRIPTION (provided by applicant): The long-term objectives of this project are to develop long-acting Na+ channel blockers pertinent for pain management and to gain a better understanding of how these blockers work mechanistically. Traditional local anesthetics (LAs) are often inept for chronic or intractable cancer pain due to their insufficient duration of nerve block. Our specific aims are (1) to identify and synthesize compounds that potently block the open and/or inactivated Na+ channels, (2) to assess the use- and state-dependent block of potent Na+ channel blockers, (3) to test their in vivo potency as long-acting LAs, and (4) to map their receptor site within the Na+ channel alpha-subunit. Recent screening has identified several new lead structures that block open Na+ channels with high affinities. Earlier screening demonstrated that drugs taken orally for neuropathic pain, such as amitriptyline, flecainide, and mexiletine, also block open Na+ channels effectively at their therapeutic plasma concentrations. We hypothesize that these drugs alleviate ectopic high-frequency discharges found in injured nerves due to their high-affinity block of open Na+ channels. Amitriptyline, which too potently blocks the inactivated Na+ channels, indeed acts as a long-acting LA. We plan to identify and synthesize novel open and/or inactivated-channel blockers based on these lead structures. Their use-dependent block of Na+ currents during repetitive pulses and the 50% inhibitory concentration (IC50) of resting-, open-, and inactivated-channel block will be determined in wild-type and/or in inactivation-deficient mutant Na+ channels expressed in human HEK293 cells. Sensory and motor functions of nerve block will be evaluated in rats or sheep before and after injection of potent Na + channel blockers via various routes. Finally, we plan to delimit the receptor for selected blockers within the Na+ channel alpha-subunit by site-directed mutagenesis and by computer simulation of the ligand-receptor complex. This information will in turn facilitate receptor-based drug design. Together, these studies should provide us new lead structures for the development of long-acting LAs that selectively target open and/or inactivated Na+ channels. Such drugs, either taken orally or injected locally, may be beneficial for patients with chronic and intractable cancer pain.

描述（由申请人提供）：该项目的长期目标是开发与疼痛管理相关的长效NA+通道阻滞剂，并更好地了解这些阻滞剂的机理方式。传统的局部麻醉剂（LAS）由于神经阻滞的持续时间不足，通常会​​因慢性或顽固性癌症疼痛而无能为力。我们的具体目的是（1）识别和合成化合物，以有效阻断开放式和/或灭活的Na+通道，（2）评估有效的Na+通道阻滞剂的使用和状态依赖性块，（3）测试其体内效力作为长活化的LAS，以及（4）在Na+ Channel Alpha-Subpha-Subpha-sububunit中映射其受体。最近的筛选已经确定了几种新的铅结构，这些结构阻断了具有高亲和力的开放NA+通道。较早的筛查表明，口服因神经性疼痛而口服的药物，例如阿米替林，氟卡因和墨西甲胺，还可以在其治疗性血浆浓度下有效地阻断开放式Na+通道。我们假设这些药物减轻了由于开放的Na+通道的高亲和力块，在受伤的神经中发现了异位高频排放。阿米替林太有效地阻止了被灭活的Na+通道，确实是长效的LA。我们计划根据这些铅结构来识别和合成新颖的开放和/或灭活通道阻滞剂。它们在重复脉冲期间的Na+电流的使用依赖性块以及在野生型和/或在人类HEK293细胞中表达的缺乏缺陷的突变体Na+通道中，将确定静止，开放和灭活通道块的50％抑制浓度（IC50）。通过各种路线注射有效的Na +通道阻滞剂前后，将在大鼠或绵羊中评估神经阻滞的感觉和运动功能。最后，我们计划通过定点诱变和通过计算机模拟配体受体复合物的计算机模拟来划定Na+通道α-纯基中选定阻滞剂的受体。此信息反过来将促进基于受体的药物设计。这些研究共同为我们提供了新的铅结构，以开发长效的LA，以选择性地针对开放和/或灭活的Na+通道。此类药物是口服或局部注射的，可能对患有慢性且顽固性癌症疼痛的患者有益。