Nepicastat: a versatile therapeutic agent - pharmacological activities and clinical prospects

Nepicastat (NEP) is a popular, highly selective inhibitor of dopamine β-hydroxylase (DBH) being more selective than disulfiram, which is clinically employed in the treatment of alcohol use disorders. NEP initially garnered interest owing to its similar therapeutic indications, particularly in the context of substance use disorder. Its mechanism of action is to reduce the biosynthesis of noradrenaline by inhibiting the conversion of dopamine, two critical neuromodulators involved in regulating brain states, reward, learning, and memory processes. Given the central role of dopamine in the pathophysiology of cocaine addiction, and supported by evidence that disulfiram reduces the rewarding effects of cocaine, NEP has been hypothesized to exert therapeutic effects in this context as well. Notably, NEP may mitigate the risk of cocaine relapse, at least in part, by elevating dopamine levels in the prefrontal cortex - a region essential for executive control and impulse regulation. Beyond addiction, the roles of dopamine, noradrenaline and DBH are increasingly recognized in the pathogenesis of various diseases, including neurodegenerative disorders, cancer, and cardiovascular conditions. Consequently, NEP has attracted growing scientific interest as a candidate for drug repurposing. In this article, we provide a comprehensive overview of the current state of knowledge surrounding NEP, highlighting its diverse pharmacological actions and emerging potential across a range of therapeutic areas.