Advances in dopamine transporter inhibitors: Design strategies, structural features, and pharmacological insights

Dopamine transporter (DAT) plays a pivotal role in regulating synaptic dopamine homeostasis and is critically involved in various neuropsychiatric disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), attention-deficit/hyperactivity disorder (ADHD), major depressive disorder (MDD), and substance use disorders. This review highlights cutting-edge advances in the development of DAT inhibitors, offering new insights into their structure-activity relationships, pharmacological mechanisms, and therapeutic potential. The core findings emphasize the significance of conformational selectivity in overcoming addiction-related limitations of typical inhibitors and uncover novel strategies for engineering atypical and allosteric inhibitors with improved efficacy and safety profiles. Furthermore, a comprehensive analysis of clinical trials reveals the main challenges in DAT inhibitor development, such as off-target toxicity and multitarget-related adverse effects, providing a foundation for addressing these issues. By distilling critical design strategies and lessons learned, this review provides a theoretical framework and actionable guidance for the future development of safe, selective, and effective DAT-targeting therapies.