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

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2022 · $548,842

## Abstract

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.

## Key facts

- **NIH application ID:** 10465978
- **Project number:** 1R01NS127439-01
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Corey R. Hopkins
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $548,842
- **Award type:** 1
- **Project period:** 2022-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10465978

## Citation

> US National Institutes of Health, RePORTER application 10465978, Discovery and characterization of selective GIRK1/2 activators and their evaluation in preclinical models of pain (1R01NS127439-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10465978. Licensed CC0.

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