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

点击翻译按钮获取中文摘要

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.