# Development of sterol carrier protein 2 inhibitors as anxiolytics

> **NIH NIH R01** · MEDICAL COLLEGE OF WISCONSIN · 2024 · $679,286

## Abstract

According to the NIMH, approximately one in five Americans suffered from an anxiety disorder in the last year
and nearly 1/3 will experience an anxiety disorder in their lifetime. Anxiety disorders are primarily treated with
biogenic amine reuptake inhibitors which can have delayed or inadequate efficacy, so there is a great need for
additional anxiolytics with different mechanisms of action. There is clear evidence that activation of CB1R
cannabinoid receptors can be anxiolytic; however, direct activation of CB1Rs, with THC for example, can
produce undesirable effects, such as changes in cognition and posture, and can result in dependence. On the
other hand, CB1R indirect agonists, which elevate concentrations of the endogenous ligands of CB1R
(endocannabinoids, eCBs), represent a rational approach with beneficial effects of CB1R enhancement and
fewer off-target effects. Our team has discovered that sterol carrier protein-2 (SCP-2), which is enriched in the
amygdala, binds the eCBs N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) at nanomolar
concentrations and enhances intracellular sequestration of AEA. Thus, we hypothesize that inhibition of SCP-2
will reduce eCB sequestration, enhance CB1R signaling and thereby reduce anxiety. In support of this
hypothesis, SCP-2-1- mice exhibit reduced anxiety-like behaviors and enhanced extinction of conditioned fear,
both reversible by CB1R blockade. SCPl-1, a previously identified small molecule inhibitor of SCP-2, has
anxiolytic effects that are blocked by CB1R antagonism. However, SCPl-1 is not sufficiently potent, selective,
or metabolically stable to serve as a molecular probe of SCP-2 for further mechanistic studies. The goal of the
studies in this proposal is to design, synthesize and test a focused library of molecules to identify a potent inhibitor
of SCP-2 binding pocket that can be used in mechanistic studies to elucidate the role of this protein in the life
cycle of the eCBs, particularly in brain circuits involved in fear and anxiety. In Aim 1, we will utilize computer
assisted drug design (CADD) to develop FragMaps and use this information to design and synthesize new
potential SCP-2 inhibitors. CADD will also be used to predict metabolic issues and off-target effects of these
compounds. In Aim 2, we will use in vitro approaches to characterize SCP-2 binding of the novel inhibitors;
determine key physicochemical properties; and measure effects on cellular eCB uptake. Information from these
studies will be used to refine our computational model. In Aim 3, we will use in vivo approaches to determine
pharmacokinetic properties of a few novel molecules to inform us about dosing for behavioral assays, which we
will complete in this aim as well. We will determine potential toxicity and metabolism of these compounds.
Successful completion of these studies is expected to result in new small-molecule inhibitors of SCP-2 that will
be used to further validate the role of SCP-2 within ...

## Key facts

- **NIH application ID:** 10998194
- **Project number:** 1R01MH133315-01A1
- **Recipient organization:** MEDICAL COLLEGE OF WISCONSIN
- **Principal Investigator:** CHRISTOPHER W CUNNINGHAM
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $679,286
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998194

## Citation

> US National Institutes of Health, RePORTER application 10998194, Development of sterol carrier protein 2 inhibitors as anxiolytics (1R01MH133315-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10998194. Licensed CC0.

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