# Novel Antagonists of the N-terminal Domain of the CRF Receptor Type 1 for Alzheimer's Disease

> **NIH NIH RF1** · VETERANS MEDICAL RESEARCH FDN/SAN DIEGO · 2020 · $1,728,235

## Abstract

CRF is the major neuropeptide hormone associated with stress and is mediated predominantly
signaling through CRF receptor subtype 1 (CRFR1) in the CNS. CRF signaling has been
implicated in Alzheimer's disease (AD) as there is increased CRF expression, CRF binding to
and upregulation of CRFR1 receptors in the cortex, hippocampus and hypothalamus appears to
occur early in disease AD progression and are prominent neurochemical changes in areas
vulnerable to AD neuropathology. CRFR1 expression also intersects with Abeta (Aβ) and tau
pathologies, both known to be critical hallmarks of AD. There have been substantial efforts in
academia and pharmaceutical companies to develop potent small molecule antagonists of
CRFR1, however, even the current 3rd generation antagonists are still directed against the C-
terminal regions of the CRFR1 receptor are still based on the 2nd generation chemical scaffolds
along with their inherent toxicity liabilities. This project capitalizes on the molecular model of
CRFR1 activation, established through extensive studies, where the first step is binding of CRF
to specific ligand binding motifs in the receptor's N-terminal region and binding motifs. We have
developed and validated an novel homogeneous TR-FRET assay to measure the direct binding
of biotin-labeled CRF to the N-terminal extracellular domain (ECD) of maltose binding protein
labeled CRFR1 compatible with very high-throughput screening. We have developed this
assay, verified that unlabeled CRF displaces biotin-CRF, and that several known C-terminal
CRFR1 antagonists do not displace CRF from the N-term CRFR1 ECD. Motivated by these
recent experiments, we propose to screen a large library of compounds against N-terminal
CRFR1 ECD in collaboration with the Conrad Prebys Center for Chemical Genomics at Sanford
Burnham Prebys Medical Discovery Institute. In Aim 1, we will fully implement this primary N-
terminal CRFR1 ECD assay and complete an HTS campaign to identify and confirm candidate
N-terminal CRFR1 antagonists. Aim 2 will validate these hits for potency, specificity, functional
antagonism and elucidate emergent structure activity relationships (SAR) to assess their
chemical tractability. Aim 3 will advance validated hits through hit-to-lead through cycles of
medicinal chemistry and testing through 2 critical path assays for potency and functional
antagonism, then additional lead optimization cycles where additionally, potency and efficacy in
biologically relevant 3 assays for target engagement (e.g. brain tissue slices). The best 2-3
probe compound(s), will be scale-up to benchmark their ADME/T, PK/PD and brain penetrance
and in vivo proof-of-concept studies in mouse AD models.

## Key facts

- **NIH application ID:** 9867457
- **Project number:** 1RF1AG065385-01
- **Recipient organization:** VETERANS MEDICAL RESEARCH FDN/SAN DIEGO
- **Principal Investigator:** Robert Rissman
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,728,235
- **Award type:** 1
- **Project period:** 2020-01-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9867457

## Citation

> US National Institutes of Health, RePORTER application 9867457, Novel Antagonists of the N-terminal Domain of the CRF Receptor Type 1 for Alzheimer's Disease (1RF1AG065385-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9867457. Licensed CC0.

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