Tetrahydroprotoberberines: A Novel Source of Pharmacotherapies for Substance Use Disorders?

Tetrahydroprotoberberines (THPBs) are a class of compounds that target both dopamine D1 and D2 families of receptors, making them attractive candidates for treating substance use disorder (SUD). The binding of some THPBs to serotonin and adrenergic receptors, in addition to dopamine receptors, gives rise to complex pharmacological profiles. Significant progress has been made over the last decade in examining these compounds for their therapeutic potential. Here, we evaluate recent discoveries relating to the neural mechanism and therapeutic effects of THPBs, focusing on compounds that have shown promise in animal models of SUD and preliminary clinical studies. Advancements in structure-activity relationship studies and in silico modeling of THPB binding to dopamine receptors have facilitated the synthesis of novel THPBs with enhanced therapeutic properties and provide insights regarding use of the THPB scaffold to serve as a template for innovative drug designs.