# Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics

> **NIH NIH U44** · ANAGIN · 2024 · $814,748

## Abstract

Project Summary
This application, “Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics”,
addresses the critical need for more effective medications to treat chronic neuropathic pain. Pain is responsible
for more encounters with the health care system than any other single cause, yet treatment options for
neuropathic pain have limited efficacy and carry a high risk for side effects, including opioid addiction. These
factors add an additional $560-635 billion annually to an already strained United States health care system.
Glutamate activation of N-methyl-D-aspartate (NMDA) receptors mediates central nervous system (CNS)
sensitization, which is implicated in the development and maintenance of neuropathic pain. NMDA-mediated
central sensitization depends on formation of a multi-protein cascade complex at the receptor consisting of the
NMDA receptor bound to the scaffolding protein, postsynaptic density protein 95 (PSD95), and recruitment of
neuronal nitric oxide synthase (nNOS). By bringing these proteins close together, multiple signaling cascades
are activated leading to neural network reorganization (plasticity) and neuronal cell death. Small molecules and
cell penetrating peptides that disrupt this complex act as effective analgesics in preclinical animal models with
better side effect profiles than non-selective NMDA receptor antagonists and NOS inhibitors. Our team, the first
to publish a small molecule targeting this complex, IC87201, demonstrated its efficacy in preclinical pain models.
A similar small molecule, ZL006, is effective in preclinical stroke models. We designed and synthesized a unique
and novel set of IC87201 and ZL006 analogs, advancing one molecule into IND-enabling studies for post-
traumatic stress disorder. After identifying concerns with the candidate molecule, we systematically redesigned
it resulting in a new set of molecules. Further funding is needed to improve on these molecules prior to advancing
them toward new IND-enabling studies. Importantly, advanced toxicology studies with the candidate molecule
suggest a low risk of target specific side effects and predict an excellent therapeutic index for compounds with
acceptable activity and drug-like properties. In this SBIR Phase I/II fast track application, Anagin, in concert with
our collaborators and the Blueprint Neurotherapeutics Network, will design and test molecules for improved drug-
like properties, confirm target engagement in in vitro and ex vivo assays, demonstrate efficacy in preclinical pain
models and establish a therapeutic margin using behavioral models. We will advance a new clinical candidate
molecule through IND-enabling studies. Compounds that do not meet our set criteria will not be advanced. At
the conclusion of these studies, we will have a new clinical candidate thoroughly interrogated and poised for
testing in clinical trials for chronic pain. Data summarized in this proposal strongly suggests that our appr...

## Key facts

- **NIH application ID:** 10802201
- **Project number:** 5U44NS119284-04
- **Recipient organization:** ANAGIN
- **Principal Investigator:** STEPHANIE K FLORIO
- **Activity code:** U44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $814,748
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10802201

## Citation

> US National Institutes of Health, RePORTER application 10802201, Discovery of PSD95 protein-protein interaction inhibitors as novel non-opioid analgesics (5U44NS119284-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10802201. Licensed CC0.

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