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.