XT-203: A Novel Pain and Substance Abuse Therapeutic
Abstract
The management of pain in the battlefield, as well as in the Veteran and general populations, is of significant concern to our Armed Forces. The benefits of opioids such as morphine in routine clinical use for this purpose are obvious, but so are the drawbacks: inadequate pain relief in severe injuries, respiratory depression at high doses, potential addiction, tolerance, and other unfavorable side effects. The civilian population that our Armed Forces protect is also in great danger from the opioid abuse in our country. Opioids such as morphine share a common structural core, but this core structure can occur in one of two mirror-image structures. All opioids that bind to their standard opioid receptors are known as (-)-isomers [(-)- enantiomers]. However, in addition to its affinity for opioid receptors, morphine also has agonist activity in the toll-like receptor 4 (TLR4) pathway. This latter activity is responsible for many of the negative side effects of opioid use. As a downstream result of TLR4 pathway activity, inflammatory mediators such as interleukin-1 beta and tissue necrosis factor alpha are released. We, and others, have demonstrated that these mediators are involved in the establishment of opioid tolerance and reduce the overall efficacy of these drugs. In addition, it has long been demonstrated that these mediators, along with others, are responsible for the establishment and maintenance of chronic pain, as well as increases in pain when opioid treatments are discontinued. Thus, through TLR4, opioids such as morphine actively work against their own pain relief and make the clinical situation worse by driving multiple adverse side effects, both short- and long-term. Not surprisingly, antagonists of TLR4 have been demonstrated to block the release of these inflammatory mediators and, accordingly, provide pain relief as well as reduce the development of tolerance and improve the analgesic efficacy of opiates. (+)-Enantiomers of opioids act as TLR4 antagonists. Although they are structurally opioids, these (+)-enantiomers do not bind classical opioid receptors, which bind only (-)-isomers. Therefore, they cannot competitively block opioid analgesia. Instead, these (+)-isomers acts as antagonists in the TLR4 signaling pathway, which is also activated by drugs of abuse (e.g., cocaine, alcohol) and trauma. Our data, developed in part by funding provided by the Department of Defense, demonstrate that opioid (+)-enantiomers provide significant pain relief in models of acute, moderate to severe pain, improve the efficacy of co-administered morphine, and potently block the development of morphine tolerance by preventing the activation of the TLR4 pathway. Because of its effects in this pathway, (+)-opioids should be good candidates for clinical development as standalone treatments for acute and chronic pain, in the prevention and treatment of drug abuse, and as adjunct therapeutics for enhancing the clinical efficacy of opioids for pain control and preventing opioid side effects. One drawback of the initially tested (+)-compounds is their rapid metabolism in the body. Two compounds, (+)-naloxone and (+)-naltrexone, have been examined in several different animal model systems. These compounds were effective in reducing pain responses and eliminating drug-seeking behavior, but they were generally only effective when administered directly to the central nervous system. This approach is not possible in the battlefield or in typical trauma situations. In our previous work supported by the Department of Defense, we identified a series of new (+)-compounds that were far more effective, including XT-203. This compound exhibited positive effects in a variety of animal models of pain when administered systemically rather than just to the central nervous system, consistent with the observation that it is not as rapidly metabolized as (+)-naltrexone or (+)-naloxone. It also demonstrated a very clear amplified effect when adm
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810804
Entities
People
- Raymond Chavez
Organizations
- United States Army
- Xalud Therapeutics (United States)