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

项目概要： 慢性疼痛是一种管理不善的健康疾病，常见的治疗（如阿片类药物）存在重大问题 与他们相关的：成瘾，便秘，认知障碍，运动障碍，致命的呼吸风险 抑郁症和其他。开发新的，非阿片类药物为基础的疼痛疗法是科学的主要努力， 然而，新目标的确定仍然是这一奋进的瓶颈。G蛋白门控 内向整流钾（GIRK）通道是内向整流K+通道（KIR）家族的成员。 GIRK通道，已知与μ-阿片样物质（μOR）偶联，μ-阿片样物质是阿片类镇痛药的关键靶点， 多种证据表明，治疗剂利用GIRK通道介导的超极化， 在啮齿类动物中产生镇痛作用。此外，Girk 2基因（KCNJ 6）的变异与 阿片类镇痛药的治疗效果和人类的疼痛敏感性降低。我们实验室的工作 显示全身给予GIRK 1/2激活剂，单独或与吗啡联合，可以产生 镇痛，并可增强吗啡在急性疼痛和持续性疼痛的临床前小鼠模型中的作用。 痛苦此外，我们已经观察到全身施用我们的GIRK激活剂不会导致 严重的运动障碍，也没有出现被认为是奖励的条件性位置偏好 含量测定（CPP）。为了开发一流的IND准备GIRK 1/2激活剂，我们将优化我们的铅支架 具有适当的活性、选择性和DMPK性质。我们将利用迭代药物化学 方法与急性炎性（角叉菜胶）疼痛模型相结合，以确定PK/PD模型， 用于将化合物进展为进一步的慢性疼痛模型。选择性GIRK 1/2激活剂将提供 一个独特的机会，以帮助推进该领域向一流的治疗剂。

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.