Novel Peptide Antagonists as Treatments for Substance Abuse
Abstract
Substance abuse among military personnel and Veterans is a serious concern, with approximately 10% of Soldiers returning from the wars in Iraq and Afghanistan reportedly abusing alcohol and/or drugs. Exposure to stress, including the stress associated with military service, is a major factor increasing the incidence of drug abuse. Stress is also a primary factor triggering drug-seeking behavior in individuals who have successfully stopped taking addictive substances. Recent evidence implicates the activation of kappa opioid receptors (KOR) in the brain in the response to stress, and blockade of these receptors has been shown to prevent relapse to drug-seeking behavior in animal models of cocaine and alcohol abuse. Similarly, in heroin-dependent patients a drug combination chosen to block KOR resulted in greater improvements in drug abstinence than did blocking the mu opioid receptors activated by heroin. Thus, compounds that block KOR activation could be very useful in helping patients maintain abstinence from addictive substances. Unfortunately, while a number of compounds have been identified that can block KOR, most of them do not have the desired properties (e.g., possess activity after being taken orally) to make them useful as drugs. [D-Trp]CJ-15,208 is a promising lead compound that is a selective KOR antagonist in animals and is active in mice after oral administration. Importantly, it prevents stress-induced relapse of drug-seeking behavior after oral administration in a mouse model of cocaine abuse. Its properties as a drug are also not ideal, but we expect that structural changes to the compound will result in analogs that are more potent in drug abuse models. The objective of the proposed research is to introduce structural changes into the lead compound that will result in more of the compound reaching KOR in the brain, thereby allowing lower doses to be used to treat substance abuse. The proposed studies focus on the synthesis of new analogs, their evaluation in cell and behavioral assays, and determination of their therapeutic potential in animal models of drug abuse. The long-term goal and ultimate application of this research would be to identify compounds with appropriate drug-like properties that have the potential to enter clinical trials for the treatment of drug abuse.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510464
Entities
People
- Jay P McLaughlin
Organizations
- United States Army
- University of Florida