# Development of CNS-Active 5-HT3R Antagonists for the Treatment of Neuropathic Pain

> **NIH NIH R61** · WASHINGTON UNIVERSITY · 2024 · $1,587,553

## Abstract

PROJECT SUMMARY/ABSTRACT
 Neuropathic pain (NeuP) affects 6-8% in the adult population. It leads to substantial functional impairment
and has deleterious impact on patients’ quality of life. Patients with NeuP continue to have inadequate response
to currently available pharmacotherapy options, with less than 25% achieving meaningful improvement.
Moreover, major safety concerns are associated with the use of analgesics such as opioids. There is clearly an
unmet need for new effective and safe approaches for treating neuropathic pain.
 5-HT3 receptors have emerged as a promising target in NeuP. Studies demonstrated that local intrathecal
delivery of 5-HT3 antagonists such as ondansetron alleviates mechanical and thermal hypersensitivity in animal
models of nerve injury. These compounds target 5-HT3 receptors in the CNS, which are overexpressed after
nerve injury, contributing to pain facilitation. The major challenge in achieving efficacy with systemic
administration of currently available 5-HT3 antagonists is P-glycoprotein (Pgp)-mediated efflux that limits their
penetration to the CNS, and consequently limits their therapeutic effect in NeuP. With adequate CNS penetration,
these drugs are expected to be efficacious in relieving NeuP.
 We hypothesize that identification of CNS-active lead candidates combined with the current understanding
of mechanisms of 5-HT3 receptor inhibition gained from recent structural studies and using state-of-the-art
computational drug design approaches, will allow the design/development of novel 5-HT3 antagonists with CNS
activity and competitive intellectual property (IP) position. The goal of this R61 planning grant is to establish a
multidisciplinary and collaborative team of scientists in medicinal and computational chemistry, structural biology,
pharmacology, pharmacokinetics, pain biology and clinical/translational pain research to develop and
characterize lead candidates and establish the models and feasibility of determining their preclinical efficacy in
models of neuropathic pain.
 We will use molecular dynamics simulations, structure-based virtual screening and drug design to identify
and synthesize novel lead 5-HT3 antagonists (Aim 1), characterize in vitro pharmacology and in vivo
pharmacokinetics of the novel ligands (Aim 2), and determine the analgesic efficacy and abuse liability of these
ligands in rodent models (Aim 3). We expect to establish the multidisciplinary team and its workflow for drug
development and characterization, to generate the initial data for novel CNS-penetrant 5-HT3 antagonist
development in the subsequent U19 or UG3/UH3 grant mechanism.

## Key facts

- **NIH application ID:** 10861511
- **Project number:** 1R61NS131246-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Bahaa Elgendy
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,587,553
- **Award type:** 1
- **Project period:** 2024-07-05 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10861511

## Citation

> US National Institutes of Health, RePORTER application 10861511, Development of CNS-Active 5-HT3R Antagonists for the Treatment of Neuropathic Pain (1R61NS131246-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10861511. Licensed CC0.

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