Structure–Activity Relationship of Synthetic Cathinones: An Updated Review

The escalating prevalence of new psychoactive substances (NPSs) poses a significant public health challenge, evidenced by the vast chemical diversity, with over 500 substances reported annually to the United Nations Office on Drugs and Crime-Early Warning Advisory (UNODC-EWA) in the past five years. Among NPSs, synthetic cathinones are gaining a lot of popularity among users. Notably, synthetic cathinones accounted for approximately 50% of the total quantity of NPSs reported as seized by EU Member States in 2021. Preliminary data from UNODC indicates that a total of 209 synthetic cathinones have been reported to date. As their popularity grows, studying the structure-activity relationship (SAR) of synthetic cathinones is essential. SAR studies elucidate how structural features impact biological effects, aiding in toxicity prediction, regulatory compliance, and forensic identification. Additionally, SAR studies play a pivotal role in guiding drug policies, aiding authorities in categorizing and regulating newly emerging synthetic cathinones, mitigate public health risks and offer valuable insights into potential therapeutic applications. Thus, our Review consolidates recent findings on the effects of different substitutions in the chemical scaffold of synthetic cathinones on their mechanism of action as well as pharmacological and toxicological effects of synthetic cathinones, thus enhancing understanding of the SAR of synthetic cathinones' pharmacology and potential implications.