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

选择性 GIRK1/2 激活剂的发现和表征及其在临床前疼痛模型中的评估

• 批准号: 10590728
• 负责人: Corey R. Hopkins
• 金额: $ 52.87万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590728
• 关键词: Absence of pain sensation; Acute; Acute Pain; Acute inflammatory pain; Affect; American; Analgesics; Animal Model; Animals; Anxiety; Binding; Binding Proteins; Biological Assay; Brain; Caco-2 Cells; Cardiovascular Models; Cardiovascular system; Carrageenan; Cellular Assay; Central Nervous System; Characteristics; Chronic; Communities; Constipation; Coupled; Data; Development; Diabetes Mellitus; Disease; Dose; Dose Limiting; Drug Industry; Drug Kinetics; Epilepsy; Equilibrium; Evaluation; Family; G-Protein-Coupled Receptors; GIRK1 subunit, G protein-coupled inwardly-rectifying potassium channel; GIRK4 subunit, G protein-coupled inwardly-rectifying potassium channel; GTP-Binding Proteins; Generations; Genes; Hair; Health; Heart Diseases; Human; Hyperalgesia; Hypersensitivity; Impaired cognition; In Vitro; Inflammatory; Investigational Drugs; Laboratories; Lead; Malignant Neoplasms; Mediating; Modeling; Morphine; Mus; Muscle; Nociception; Opioid; Opioid Analgesics; Oral; Pain; Pain Measurement; Pain management; Pathway interactions; Patients; Penetration; Permeability; Persistent pain; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Physiological; Plasma Proteins; Potassium; Pre-Clinical Model; Property; Rattus; Research; Rewards; Risk; Rodent; Role; Rotarod Performance Test; Safety; Self Administration; Signal Pathway; Societies; Solubility; Testing; Therapeutic; Therapeutic Agents; Toxicology; Treatment Efficacy; United States; Urea; Variant; Ventilatory Depression; Work; addiction; analog; chemical synthesis; chronic neuropathic pain; chronic pain; chronic pain management; chronic pain patient; combat; common treatment; conditioned place preference; cost estimate; disability; health management; improved; in vivo; in vivo evaluation; inward rectifier potassium channel; lead optimization; member; motor impairment; mouse model; nerve injury; non-opioid analgesic; novel; novel strategies; novel therapeutics; opioid abuse; opioid epidemic; opioid overdose; pain model; pain sensitivity; painful neuropathy; pharmacokinetics and pharmacodynamics; pharmacologic; pre-clinical; receptor; receptor-mediated signaling; response; scaffold; side effect; small molecule; spared nerve; success; therapeutic candidate; therapeutic development; water solubility

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.

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