# Design of Novel Multivalent Ligands with Unique Biological Activity Profiles for Treatment of Prolonged and Neuropathic Pain without Toxicities

> **NIH NIH P01** · UNIVERSITY OF ARIZONA · 2021 · $76,336

## Abstract

Summary - Project A: 
The goals of this research project are to design and discover novel peptide and peptidomimetic ligands 
that are multivalent ligands that can act as agonists at the mu and delta opioid receptors and antagonists 
at the neurokinin-1 (NK-1) receptor, all in a single molecule. These ligands can act as potent analgesics 
in chronic pain states, including neuropathic pain, using new mechanisms of action, but do not have any 
of the toxic side effects of current opioids. For this purpose, we are developing a comprehensive 
approach that includes: computer aided design of novel multivalent ligands, asymmetric synthesis of 
novel amino acids, design and synthesis of peptides and peptidomimetics with unique conformational 
properties, especially in membrane environments, unique biological properties for treatment of pain 
without toxicities and tolerance development, and unique abilities to penetrate membrane barriers. We 
will pursue these goals, with the following Specific Aims: 1) to design and synthesize novel multivalent 
ligands that have potent mu and delta opioid receptor agonist activity neutral and (mu preferring) and 
potent NK-1 receptor antagonist activity; 2) in conjunction with the Biochemical Core, to evaluate the 
pharmacological activities of these compounds with comprehensive binding affinities and efficacies at 
mu, delta and NK-1 receptors (also as needed, kappa opioid receptors and NK-3 receptors); 3) to 
evaluate the conformational properties of the best ligands by biophysical studies (NMR, CD, etc.) in 
aqueous and membrane environments; 4) in conjunction with the Biochemical and Synthesis Cores, to 
evaluate their biological activities in vivo to demonstrate the potency and efficacy in in vivo models of 
acute, prolonged and neuropathic pain states, and determine their lack of toxic side effects that are 
found in current analgesic drugs, including inhibition of gut transit, emesis, development of addictive 
behaviors, lack of respiratory depression and development of tolerance. We also will evaluate their 
ability to cross membrane barriers and their stability and biodistribution in vivo. A major goal is to obtain 
two or three potent, stable and bioavailable ligands with the desired biological activity profiles for 
examination in human clinical trials.

## Key facts

- **NIH application ID:** 10151590
- **Project number:** 5P01DA041307-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Victor J Hruby
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $76,336
- **Award type:** 5
- **Project period:** 2017-05-01 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10151590

## Citation

> US National Institutes of Health, RePORTER application 10151590, Design of Novel Multivalent Ligands with Unique Biological Activity Profiles for Treatment of Prolonged and Neuropathic Pain without Toxicities (5P01DA041307-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10151590. Licensed CC0.

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