Developing nonmuscle II inhibitors for substance use relapse

项目总结 物质使用障碍(SUD)是一种慢性、复发性疾病，治疗选择有限，花费约700美元 每年10亿美元。对于鸦片、尼古丁和酒精，存在一些中等有效的替代疗法 依赖。然而，对于兴奋剂依赖，没有这样的选择，而且，也没有药物依赖。 预防或甚至减少与任何药物类别相关的复发的治疗。已经形成的协会 在吸毒期间，通过激发寻求毒品的动机，成为强大的复发因素。最近， 突触肌动蛋白细胞骨架是记忆的关键调节器，被确定为 有选择地破坏这些联系。事实上，中枢神经系统内的肌动蛋白解聚会立即产生 持续丧失与兴奋剂甲基苯丙胺(冰毒)相关的健全记忆，而不是 影响其他类型的记忆。然而，β-肌动蛋白，与神经元可塑性有关的异构体，是至关重要的 在身体各处运作。因此，努力转向肌动蛋白细胞骨架的上游调节器， 非肌肉肌球蛋白II(NMII)，一种选择性表达的促进突触肌动蛋白的分子马达 聚合反应。所有直接肌动蛋白解聚的结果都用小分子的Blebbistatin进行了概括 NMIIs的分子抑制物。重要的是，单用博尔比星治疗就足以产生 似乎永久性地丧失了与冰毒相关的记忆。除了对动物复发的疗效外 Blebbistatin的多种特性使其成为药物化学的极佳支架。派拉蒙在 这些是分子的小尺寸，对肌球蛋白II的选择性，高的脑渗透率，以及快速清除 血浆和大脑(短效就足够了，减少了不必要的外周和中枢影响)。不幸的是， Blebbistatin在心肌肌球蛋白II的活性可能是一种易感性。优化努力是有限的 因为抑制NMII的治疗潜力是在过去几年才实现的。因此， 这项建议的中心目标是开发一种安全、选择性的NMII小分子抑制剂，并改进 效力和溶解性，保留了其现有的、有利的DMPK特性，并将毒理降至最低 参数。为了实现开发Ind Ready化合物的总体目标，一种广泛的药物 将采用以博尔比星类似物为中心的药物发现和开发方法，以 详细的结构活动关系方法。一支由多年临床前药物组成的团队 包含本项目中采用的所有方法的开发经验(医学 化学、生物化学、细胞生物学、神经生物学、体内药理学、药物代谢和 药代动力学(DMPK)、毒理学和临床研究)，使该团队成为唯一有资格指导 程序。通过利用佛罗里达州斯克里普斯独特的治疗发现和开发能力， 这项提议有望产生一种安全、有效的化合物，并有足够的临床前安全性数据来支持 人类临床试验的重点是SUD复发。

PROJECT SUMMARY Substance use disorder (SUD), a chronic, relapsing disorder with limited treatment options, costs the US ~$700 billion annually. A few, moderately effective replacement therapies exist for opiate, nicotine and alcohol dependence. However, no such options exist for stimulant dependence and, further, there are no pharmaco- therapies to prevent or even reduce relapse associated with any drug class. Associations that have formed during periods of drug use serve as powerful relapse factors by triggering motivation to seek the drug. Recently, the synaptic actin cytoskeleton, a critical regulator of memory, was identified as a biological target for the selective disruption of these associations. Indeed, intra-CNS actin depolymerization produces an immediate and persistent loss of well-established memories associated with the stimulant methamphetamine (METH), without affecting other types of memories. However, β-actin, the isoform implicated in neuronal plasticity, serves critical functions throughout the body. Therefore, efforts turned to an upstream regulator of the actin cytoskeleton, nonmuscle myosin II (NMII), a more selectively expressed molecular motor that promotes synaptic actin polymerization. All results with direct actin depolymerization have been recapitulated with Blebbistatin, a small molecule inhibitor of NMIIs. Importantly, a single treatment with Blebbistatin is sufficient to produce a seemingly permanent loss of METH-associated memories. In addition to its efficacy in animal relapse models, several properties make Blebbistatin an excellent scaffold for medicinal chemistry. Paramount among these are the molecule’s small size, selectivity for myosin IIs, high brain penetration, and rapid clearance from plasma and brain (short-acting is sufficient and reduces unwanted peripheral and central effects). Unfortunately, Blebbistatin’s activity at cardiac muscle myosin IIs is likely a liability. Optimization efforts have been limited because the therapeutic potentials of NMII inhibition have only been realized in the past few years. Thus, the central goal of this proposal is to develop a safe and selective NMII small molecule inhibitor with improved potency and solubility, that retains its existing, advantageous DMPK properties with minimized toxicological parameters. To accomplish the overall goal of developing an IND ready compound, an extensive pharmaceutical approach to drug discovery and development centered on Blebbistatin analogs will be employed, centered on a detailed structure activity relationship approach. A team has been assembled with many years of preclinical drug development experience that encompasses all of the methodologies employed in this project (medicinal chemistry, biochemistry, cell biology, neurobiology, in vivo pharmacology, drug metabolism and pharmacokinetics (DMPK), toxicology, and clinical research), making this team uniquely qualified to direct the program. By capitalizing on the unique therapeutic discovery and development capabilities at Scripps Florida, this proposal is expected to yield a safe, efficacious compound with sufficient preclinical safety data to support human clinical trials focused on SUD relapse.