Synthetic cathinones are popular drugs of abuse that act at monoamine transporters as releasing agents or as reuptake inhibitors. The emergence of &gt;150 new synthetic cathinones has attracted considerable attention from the medical and law enforcement community. α-PVP (flakka), a second generation abused synthetic cathinone, is &gt;50 times more potent than cocaine as a central stimulant and reuptake inhibitor at the dopamine transporter (DAT). Methylphenidate (MP), used for ADHD and narcolepsy, is also a DAT reuptake inhibitor. MP is structurally similar to the cathinones and has been well examined. Available MP literature (on &gt;80 analogs) might help understand the actions of synthetic cathinones. Our aim is to synthesize and examine MP-flakka hybrid molecules to determine if MP SAR can be applied to cathinone SAR. If so, this would reduce efforts to understand the SAR of new synthetic cathinones. Seven hybrid molecules were synthesized and examined in competition assays at 10 μM against APP+ at hDAT expressed in HEK cells. A complete dose-response study will be available soon. The Spearman rank-order correlation between the preliminary results and the literature-derived MP binding data was found to be 0.955 (n = 7). MP and hybrid molecules were docked at hDAT models derived from the dDAT crystal structure (PDB ID = 4XP4), and binding modes were identified which showed that MP and the hybrid molecules have a common binding pocket where the amine forms a hydrogen bond with Asp79. The carbonyl oxygen atom of the ester in MP also forms a hydrogen bond with Ser422 which is missing in the hybrid analogs. The results suggest that synthetic cathinones bind at DAT in a fashion similar to that of MP. The higher potency of MP relative to the synthetic cathinones might be due to an additional hydrogen bond that is absent in the latter.

Methylphenidate (Ritalin®) and synthetic cathinones (bath salts): Are they similar?

2019 Spring National Meeting

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