Discovery and characterization of selective GIRK1/2 activators and their evaluation in preclinical models of pain

项目总结： 慢性疼痛是一种管理不善的健康障碍，常规治疗(如阿片类药物)存在严重问题 与之相关的风险：上瘾、便秘、认知障碍、运动障碍、致命呼吸道 抑郁，以及其他。开发新的、非阿片类药物为基础的止痛疗法是科学家们的一项主要努力 然而，确定新的目标仍然是这一努力的一个瓶颈。G蛋白门控 内向整流钾通道(GIRK)是内向整流钾通道(KIR)家族的成员。 GIRK通道，已知与阿片类止痛药的关键靶点μ-阿片(μOR)偶联，以及 多条证据表明，治疗方法利用GIRK通道介导的超极化 在啮齿动物身上产生止痛作用。此外，Girk2基因(KCNJ6)的变异与 阿片类镇痛剂的治疗效果和人类对疼痛的敏感性降低。我们实验室的工作已经完成 研究表明，全身注射GIRK1/2激动剂，单独或与吗啡联合使用，可产生 镇痛作用，并能增强吗啡对临床前期小鼠急性疼痛和持续性疼痛的影响 疼痛。此外，我们观察到，系统地给予我们的GIRK激动剂并不会导致 严重的运动障碍，在条件位置偏好中似乎也没有被认为是有回报的 测定(CPP)。为了开发一流的、支持Ind的GIRK1/2激活剂，我们将优化我们的铅脚手架 具有适当的活性、选择性和DMPK性质。我们将利用一种迭代的药物化学 结合急性炎症(卡拉胶)疼痛模型确定PK/PD模型，该模型可以 被用来将化合物进一步发展成慢性疼痛模型。选择性GIRK1/2激活剂将提供 这是一个独特的机会，有助于将该领域推向一流的治疗剂。

PROJECT SUMMARY: Chronic pain is a poorly managed health disorder and common treatments (e.g. opioids) have significant issues associated with them: risk of addiction, constipation, cognitive impairment, motor impairment, fatal respiratory depression, and others. Developing new, non-opioid based pain therapies is a major effort of the scientific community; however, the identification of new targets is still a bottleneck in this endeavor. G protein-gated inwardly rectifying potassium (GIRK) channels are members of the inwardly rectifying K+ channel (KIR) family. GIRK channels and known to couple to the μ-opioid (μOR), which is a key target of opioid analgesics, and multiple lines of evidence indicate that the therapeutics utilize GIRK channel-mediated hyperpolarization to produce their analgesic effect in rodents. In addition, variations in the Girk2 gene (KCNJ6) are associated with decreased therapeutic efficacy of opioid analgesics and pain sensitivity in humans. Work from our labs has shown that systemic administration of GIRK1/2 activators, alone or in combination with morphine, can produce analgesia, and can enhance the effects of morphine in preclinical mouse models of acute pain and persistent pain. In addition, we have observed that systemic administration of our GIRK activators does not result in significant motor impairment, nor does it appear to be perceived as rewarding in the conditioned place preference assay (CPP). In order to develop first-in-class, IND-ready GIRK1/2 activators, we will optimize our lead scaffold with the appropriate activity, selectivity and DMPK properties. We will utilize an iterative medicinal chemistry approach coupled with an acute inflammatory (carrageenan) pain model to determine a PK/PD model that can be used to progress compounds into further chronic models of pain. The selective GIRK1/2 activators will offer a unique opportunity to help advance the field toward a first-in-class therapeutic agent.