Characterization of Novel, Agmatine‐Based NMDA Receptor Antagonists in Multiple Pain States
Abstract
The worsening opioid epidemic has highlighted the need for the development of new, safe, and effective analgesic therapeutics. Opioid therapy currently is associated with the risk of conversion to addiction, diversion from patients for whom use is intended, and the development of analgesic tolerance, or the loss of efficacy with continued treatment. To this end, we have developed a line of non‐opioid, agmatine‐based compounds and assessed them for their efficacy in reversing behavioral expressions of pain in animal models, as well as evaluated their safety following chronic exposure. We have previously shown that agmatine, decarboxylated L‐arginine, is an N‐methyl‐D‐aspartate (NMDA) receptor antagonist that preferentially antagonizes receptors that express NR2B subunits. This preferential antagonism is desirable for NMDA‐based therapeutics as it can lead to a widening of the therapeutic window and avoidance of the side effects commonly associated with NMDA antagonism including motor ataxia and psychoactive effects. However, agmatine has shown limited penetration through the blood brain barrier (BBB) and a short systemic half‐life, limiting its clinical utility. We have designed strategically‐substituted agmatine (SSA) compounds with the goal of improving its penetration through the BBB by increasing the lipophilicity of agmatine, potentially improving distribution across the BBB and increasing its half‐life following systemic delivery. To this end, we have evaluated this series of SSAs for safety and efficacy in multiple animal models of pain.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- May 01, 2022
- Source ID
- 10.1096/fasebj.2022.36.s1.r5090
Entities
People
- Carolyn A. Fairbanks
- Cristina D. Peterson
- George L. Wilcox
- Kelley F. Kitto
Organizations
- Congressionally Directed Medical Research Programs
- University of Minnesota