PROJECT SUMMARY/ABSTRACT Cocaine use disorder (CUD) remains a serious problem, with approximately 5.2 million people reporting cocaine use in the U.S. and nearly 1.3 million reporting CUD in 2020. CUD is a chronic disorder with high rates of relapse to cocaine-seeking behavior. Moreover, exposure to stress induces increases in cocaine craving which have been found to predict relapse to cocaine use in cocaine-dependent patients. Unfortunately, there are currently no approved pharmacological treatments for either CUD or stress-induced potentiation of CUD. Kappa opioid receptors (KOR) have emerged as a promising target for the potential treatment of CUD. KOR and their endogenous peptide agonists, the dynorphins, prominently modulate drug reward. Exposure to stress increases levels of dynorphin peptides and is known to paradoxically potentiate cocaine reward and promote relapse to drug use in abstinent individuals. In animal models, treatment with KOR antagonists ameliorates stress-induced potentiation of cocaine reward and prevents stress-induced reinstatement of extinguished cocaine-seeking behavior, suggesting that KOR antagonists could serve as novel therapeutics for CUD and stress-induced CUD. We have identified novel systemically active cyclic peptides that selectively antagonize KOR and show therapeutic benefits in an animal model of stress-induced relapse to CUD. The proposed research focuses on these novel, orally active peptide KOR antagonists, with the goal of optimizing lead cyclic peptides to yield candidates for further development as potential treatments for CUD and stress-induced potentiation of CUD. The UG3 phase consists of two specific aims: 1) further characterize existing promising analogs synthesized previously for potential development; and 2) perform focused structural modifications on the lead cyclic peptides in preparation for the UH3 phase of the research. Analogs will be assessed for their pharmacokinetic properties and in vitro KOR affinity, selectivity and antagonist potency, with promising analogs evaluated in vivo after oral administration for their KOR antagonist potency and in rodent models of cocaine reward (conditioned place preference and intravenous self-administration assays) for therapeutic efficacy in preventing stress-induced potentiation of cocaine reward and stress-induced reinstatement of extinguished cocaine- seeking behavior. The UH3 phase continues this work and consists of two additional specific aims: 3) expanding the exploration of the structure-activity relationships of the lead cyclic peptides to improve their pharmacokinetic properties and enhance pharmacological potency in vivo, and 4) perform additional safety studies needed to advance the most promising compounds into development for clinical use. Given the success of our preliminary data identifying promising lead cyclic peptide KOR antagonists, we expect at the end of the proposed research to have identified at least one analog for development as a potential treatment of CUD.

PROJECT NARRATIVE There is an urgent unmet medical need for pharmacological treatments for cocaine use disorder. Novel compounds that block kappa opioid receptor activity will be synthesized, characterized and studied with the goal of identifying novel treatments for cocaine use disorder that can be advanced into development for potential clinical trials.