# KCa2 Channel Activators for Opioid Use Disorder

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $419,881

## Abstract

Abstract
Both human and rodent data showing reduced expression of the small-conductance, calcium-
activated potassium channel KCa2.2 (SK2) in the context of morphine and alcohol dependence and
withdrawal suggest KCa2 channel activation as a promising therapeutic approach for the treatment of
substance use disorders and associated comorbidities. In support of this therapeutic hypothesis, KCa2
channel activators reduce alcohol seeking and intake in rats, while direct injection of the KCa2 channel
blocking peptide apamin into the nucleus accumbens, a brain region which plays a crucial role in
regulating craving and drug seeking during abstinence, increases alcohol intake in mice. In response
to the HEAL Initiative RFA-DA-22-032 Funding Opportunity Announcement, we are here proposing to
perform virtual high-throughput-screening with the goal of identifying novel KCa2 activator
pharmacophores that are free of the liabilities of the existing unselective benzothiazole-type activators
and that could be developed into innovative treatments for opioid use disorders (OUD), a condition
that affects more than 3 million Americans.
 For the implementation of this project, we will draw on our 20 years of experience with the
medicinal chemistry of KCa channels. After we initially developed KCa3.1 blockers such as TRAM-34,
we later discovered the mixed KCa2/3 activator SKA-31, and the KCa3.1 selective activators SKA-121
and SKA-111. All these compounds, which have been widely used in the field to probe the
physiological and pathophysiological roles of KCa channels were designed using classical medicinal
chemistry approaches without any structural insight. However, the MacKinnon laboratory recently
published the full-length cryo-EM structure of a KCa channel in the closed and two open states and we
now have a high-quality structural template available to virtually screen for novel KCa2.2 channel
modulators that could be used as pharmacological probes and as leads for the design of drugs for the
treatment of OUD. In Aim-1, we will validate our KCa3.1-based KCa2.2 homology model by virtually
screening 2000 FDA-approved compounds in two activator binding pockets and experimentally
confirm the hits by electrophysiology and mutagenesis. In Aim-2, we will perform a virtual High
Throughput Screen (vHTS) of a larger, 130,000-compound library with machine learning (ML)
techniques for pose classification and binding affinity prediction. Taken together, these two aims have
the potential of 1) identifying a clinically used drug that could be repurposed for OUD and 2)
discovering novel KCa2.2 activator pharmacophores that could serve as templates for structure-
based-medicinal chemistry optimization aimed at developing OUD treatments with a novel
mechanism of action.

## Key facts

- **NIH application ID:** 10511349
- **Project number:** 1R21DA056637-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** HEIKE WULFF
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $419,881
- **Award type:** 1
- **Project period:** 2022-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10511349

## Citation

> US National Institutes of Health, RePORTER application 10511349, KCa2 Channel Activators for Opioid Use Disorder (1R21DA056637-01). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10511349. Licensed CC0.

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