In vivo Characterization of PRA078C in the Rat Cocaine Reinstatement Model

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Drug addiction is a major, unmet medical condition with a global impact. According to the 2017 National Survey on Drug Use and Health, over 30.5 million people over the age of 12 in the U.S. had reported using an illicit drug in the past 30 days, and >7.5 million people were addicted to illicit drugs. The annual cost of dealing with this issue exceeds $600 billion, and the impact of individual health and wellness is significant. Drug abuse is linked to increased risks of cardiovascular disease, stroke, cancer, lung disease, as well as HIV and hepatitis infection. Cocaine is one of the most commonly abused illicit drugs, and the negative impact of this drug is apparent in the 2011 Drug Abuse Warning Network (DAWN) report which revealed that over 500,000 patients required hospital emergency department services as a result of cocaine use. Despite the clear and compelling need, there are no FDA approved medications for the treatment of cocaine addiction. It is, however, known that cocaine exerts its effects via the mesocorticolimbic dopamine (MCL-DA) system, also known as the reward system. Dopamine release and reabsorption systems within the MCL-DA are altered by both acute and chronic exposure to cocaine. It has been previously demonstrated that there is substantial interplay between MCL-DA activity and serotonergic neurons that extend into this region of the brain. In addition, several studies have demonstrated that serotonin (5-HT) releasing serotonergic neurons regulate the activity of dopaminergic neurons in these regions of the MCL-DA system under both normal conditions and in the presence of cocaine. The apparent link between dopaminergic and serotonergic signaling suggests that modulating 5-HT signaling may be a viable approach to cocaine addiction. We have identified a series of novel, drug-like 5-HT7 antagonists that include a lead compound, PRA073C, which produces a statistically significant in cocaine reinstatement rat model of addiction in our preliminary studies. In this program, we will generate dose dependency data in the rat reinstatement model of cocaine addiction. This data will support our continued advancement of this compound into pre-clinical IND enabling studies as a treatment for cocaine addiction.