Sigma Receptor Ligands as Nonopioid-Based Pain Management
Abstract
Chronic pain is the number one cause of adult disability in the United States, and military personnel are at greater risk for injury and chronic pain. More than 300,000 active duty Soldiers in the U.S. Army report injuries annually, and in a survey study of active duty personnel, severe and chronic pain was most often reported for back injuries (21%), along with frustrations over the quality of care. Opioid painkillers are used by over 50% of military personnel in pain, but with notable liabilities including tolerance, respiratory depression, physical dependence, and addiction. Additionally, opioid abuse is a clear and growing danger: in 2008, 11% of active military personnel reported using prescription drugs, mostly opioids, almost three-fold higher than found just 3 years earlier. The need for analgesics without liabilities such as respiratory depression and abuse remains a great need in active and Veteran military populations. This proposal to investigate non-opioid pain management specifically addresses two stated items from the Fiscal Year 2016 Peer Reviewed Medical Research Program Topic Areas: (1) researching treatments for chronic pain management in complex patients (interpreted as experiencing neuropathic pain requiring novel therapeutics not already in use) and (2) the development of novel non-opioid pain medicines that may be administered acutely in the field without affecting the cardiorespiratory system. Recent studies have suggested that sigma-1 receptor (S1R) antagonists produce significant relief from chronic pain, but show none of the liabilities of established painkillers. Although originally believed to be a type of opioid receptor, sigma receptors are now known to be a distinct class of proteins, thought to modulate the response to pain and other environmental stimuli at the site of insult. The applicant, Dr. McCurdy, has synthesized and characterized highly selective S1R antagonists in an attempt to develop a new class of non-opioid painkillers. These include CM304, which demonstrated potent analgesic in rodent models of inflammatory pain and peripheral nerve damage devoid of respiratory depression or abuse liabilities. Although quickly metabolized, CM304 was recently successfully transformed into a radioligand (FTC146) now in human clinical trials as an imaging tool to identify sites of peripheral nerve damage. The work proposed seeks to significantly accelerate the development of drug-like S1R selective antagonists as a new class of non-opioid painkillers. Using three integrated aims, our interdisciplinary development team will (1) chemically synthesize novel analogs of CM304 that we will determine with biochemical assays retain high S1R selectivity, (2) identify analogs from this aim that possess improved pharmacokinetic and metabolic properties to promote oral bioavailability, and (3) characterize the analgesic properties of stable lead compounds from the first two aims and evaluate the most potent for potential liabilities of sedation, respiratory depression, and substance abuse in mouse models. Overall, we hypothesize that we will produce novel, metabolically stable, orally available S1R antagonists with potential as pharmacotherapeutics for peripheral pain and significantly reduced liabilities of use. The long-term goal of this research is to identify at least one preclinical candidate and multiple backup candidates with appropriate drug-like properties that have the potential to enter clinical trials. The success of FTC146 in ongoing clinical trials and strong preliminary data herein suggest a high likelihood of success for this project, with the opportunity to significantly improve safer pain management for both the civilian and military populations.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710557
Entities
People
- Christopher R McCurdy
Organizations
- United States Army
- University of Florida