# Development of in vivo probes to study the function of TRIP8b in cognition

> **NIH NIH R56** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2022 · $847,526

## Abstract

Abstract
Cognitive dysfunction is a common feature of neuropsychiatric diseases related to chronic stress. These
symptoms can be debilitating, and despite the high prevalence of illnesses like Major Depressive Disorder,
there are relatively few treatment options. To better address these symptoms, novel molecular targets are
needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play a critical role in regulating
excitability in the hippocampus, a brain region critically involved in cognition. To avoid cardiac side effects
associated with antagonizing HCN channels (which are also expressed in the heart), our group has focused
on TRIP8b, a neuron-specific subunit of HCN channels. In our recently published report (Lyman et al, in
press at Science Translational Medicine), we established that chemogenetically disrupting the interaction
between TRIP8b and HCN in the dorsal hippocampus is sufficient to rescue impairments in cognition after
chronic stress. Combined, these results are consistent with the hypothesis that a small molecule that disrupts
the TRIP8b-HCN interaction could rescue the cognitive dysfunction seen after chronic stress. In order to
capitalize on this discovery, our group recently executed a high throughput screen to identify small molecule
inhibitors of the TRIP8b-HCN interaction. We identified one candidate scaffold which shows promising activity
as a TRIP8b inhibitor. This compound series serves as the basis for our current submission in which we
propose further medicinal chemistry optimization to develop TRIP8b inhibitors for use as chemical probes in
order to study TRIP8b in vivo. In our enclosed preliminary data, we show that our inhibitor potently disrupts
the interaction between TRIP8b and HCN in cells with negligible toxicity. This inhibition produces robust
effects on Ih, the current mediated by HCN channels both in vivo and in vitro. To expand upon this work, we
propose three aims. In Aim 1, we will perform iterative medicinal chemistry optimization to develop
compounds with improved potency and pharmaceutical characteristics. Compounds that perform well in our
biochemical and biophysical assays will be advanced to cellular assays in Aim 2 in order to determine if they
are capable of disrupting the TRIP8b-HCN interaction. In Aim 3 we will utilize our compounds in vivo to study
their effect on hippocampal function. Promising compounds will be investigated for their ability to rescue
cognitive deficits that result from chronic social defeat, an animal model of chronic stress. These experiments
will enable us to develop TRIP8b inhibitors that can be used as chemical probes to study the role of HCN
channels in regulating cognitive dysfunction after chronic stress.

## Key facts

- **NIH application ID:** 10644201
- **Project number:** 1R56MH128747-01A1
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Dane M Chetkovich
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $847,526
- **Award type:** 1
- **Project period:** 2022-07-15 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10644201

## Citation

> US National Institutes of Health, RePORTER application 10644201, Development of in vivo probes to study the function of TRIP8b in cognition (1R56MH128747-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10644201. Licensed CC0.

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