Synthetic Cathinone Analogues Structurally Related to the Central Stimulant Methylphenidate as Dopamine Reuptake Inhibitors.

Synthetic cathinones are, primarily, stimulant drugs of abuse that act at monoamine transporters (e.g., the dopamine transporter or DAT) as releasing agents or as reuptake inhibitors. In the past few years, the emergence of >150 new synthetic cathinones has attracted considerable attention from medical and law enforcement communities. -Methylphenidate (MP), used clinically for the treatment of ADHD and narcolepsy, is also a DAT reuptake inhibitor. MP is somewhat structurally similar to abused cathinone stimulants, and the structure-activity relationships (SAR) of MP have been well-defined. Hence, available MP literature might assist in understanding the SAR of synthetic cathinones, about which less is known. In the present study, we synthesized and examined eight 2-benzoylpiperidine analogues (, -) to determine if MP SAR might be applicable to cathinone SAR. The benzoylpiperidine analogues were evaluated in a competition assay using live-cell imaging against APP in HEK293 cells stably expressing hDAT and in cells coexpressing DAT and voltage-gated Ca channels. All compounds were found to be DAT reuptake inhibitors, and a significant correlation was obtained between the potency of the benzoylpiperidines and MP binding data ( = 0.91), suggesting that the SAR of MP analogues might be directly applicable to certain synthetic cathinones as DAT reuptake inhibitors.