# Lead optimization of novel CRFBP-CRFR2 complex modulators for alcohol use disorder

> **NIH NIH R01** · SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE · 2021 · $733,411

## Abstract

Project Summary
This R01 application entitled “Lead Optimization of Novel CRFBP-CRFR2 Complex Modulators for Alcohol Use
Disorder” is in response to PAR-17-336 “Discovery of in vivo Chemical Probes for Novel Brain Targets (R01)”.
In the United States, alcohol use disorder (AUD) affects 15.1 million adults over the age of 18 and is the 4th
leading preventable cause of death. There remains a critical unmet need to develop more effective
therapeutics to treat AUD. Stress is a significant component in the development and maintenance of AUD.
Corticotropin releasing factor (CRF) plays an obligatory role in hypothalamic-pituitary-adrenal axis activation
and subsequent release of glucocorticoids in response to stress. CRF exerts its effects by binding to two
receptors (CRF1 and CRF2) and a 37 kD CRF binding protein [CRFBP (37kD)]. CRFBP plays a key role via
CRF2 in the modulation of ethanol consumption through actions in the ventral tegmental area (VTA). We have
demonstrated that CRF modulates synaptic input by potentiating N-methyl-D-aspartate-mediated excitatory
postsynaptic currents through CRFBP/CRF2 interactions in this region. More recently, our data suggest a dual
role for CRFBP where the CRFBP (27kD) fragment acts to terminate CRF effects and where the CRFBP
(10kD) fragment has a potential excitatory function. These data support the hypothesis that CRFBP has
functions beyond sequestering CRF and that its interaction with CRF2 may represent a novel target for the
treatment of AUD. We developed and performed a novel high-throughput screen utilizing a tethered receptor
complex between CRFBP (10kD) and CRF2 and identified novel, small molecule, CRFBP-CRF2 negative
allosteric modulators (NAMs) that act noncompetitively with respect to CRF. These NAMs do not inhibit CRF2
in the absence of CRFBP (10kD) or inhibit CRF1. Our structure-activity-relationship studies led to the
development of both lead and back-up CRFBP-CRF2 NAMs that are ready for full-scale chemistry optimization
to provide compounds suitable for ex vivo studies. Thus, our overall objective is to develop orally active
CRFBP-CRF2 modulators suitable for advanced in vivo proof-of-concept studies for the treatment of AUD. Our
Specific Aims are: 1) Design and synthesize optimized CRFBP-CRF2 NAMs that are orally active in vivo; 2)
Assess the potency and selectivity of CRFBP-CRF2 NAMs in relevant in vitro assays; 3) Profile the absorption,
distribution, metabolism, and excretion (ADME) properties of CRFBP-CRF2 NAMs in vitro and pharmacokinetic
(PK) properties in vivo; and 4) Characterize lead CRFBP-CRF2 NAM probes in ex vivo rodent models of AUD.
The CRFBP-CRF2 NAMs generated will provide powerful tools for testing the role of the CRFBP-CRF2
interaction in vivo. More importantly, we are well-positioned to develop potent and selective small molecule
CRFBP-CRF2 NAMs with optimized PK properties that will be utilized for in vivo proof-of-concept studies. This
multidisciplinary research program has ...

## Key facts

- **NIH application ID:** 10132945
- **Project number:** 5R01AA026589-03
- **Recipient organization:** SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
- **Principal Investigator:** DOUGLAS J SHEFFLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $733,411
- **Award type:** 5
- **Project period:** 2019-05-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10132945

## Citation

> US National Institutes of Health, RePORTER application 10132945, Lead optimization of novel CRFBP-CRFR2 complex modulators for alcohol use disorder (5R01AA026589-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10132945. Licensed CC0.

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