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

Abstract

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. threo-Methylphenidate (tMP), used clinically for the treatment of ADHD and narcolepsy, is also a DAT reuptake inhibitor. tMP is somewhat structurally similar to abused cathinone stimulants, and the structure− activity relationships (SAR) of tMP have been well-defined. Hence, available tMP 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 (4, 6− 12) to determine if tMP 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 2+ channels. All compounds were found to be DAT reuptake inhibitors, and a significant correlation was obtained between the potency of the benzoylpiperidines and tMP binding data (r = 0.91), suggesting that the SAR of tMP analogues might be directly applicable to certain synthetic cathinones as DAT reuptake inhibitors.

Photomediated ring contraction of saturated heterocycles

“…Finally, we turned our attention toward the application of the ring contraction methodology to biologically active small molecules to demonstrate the potential for late-stage derivatization of drug candidates. Upon irradiation, MDMC ( 9a , stimulant), rimiterol ( 9b , bronchodilator), cathinone ( 9c , DAT reuptake inhibitor) ( 31 ), and mefloquine ( 9d , antimalarial) derivatives underwent contraction to their corresponding cyclopentane isomers (Fig. 4A).…”

C–H/C–C Functionalization Approach to N-Fused Heterocycles from Saturated Azacycles

“…This limitation also holds for other elegant emerging methods for α-functionalization of saturated azacycles that also rely on the use of strong bases . Another reported approach to α-acylated saturated azacycles involves hydrogenation of pyridine rings bearing an α-acyl group, followed by oxidation (Scheme b) . This approach is limited to the preparation of six-membered saturated azacycles from a pyridine precursor.…”

Do 2-(Benzoyl)piperidines Represent a Novel Class of hDAT Reuptake Inhibitors?

“…Removal of the ester group from methylphenidate or the carbonyl oxygen atom from benzoylpiperidine to obtain an amphetamine-type analogue (IC 50 = 3780 nM) reduces DAT inhibition activity by 15-fold and 4-fold, respectively. 1 This phenomenon has been observed with the removal of the carbonyl oxygen atom from the illicit cathinone DAT inhibitor MDPV (IC 50 = 135 nM vs 1150 nM) as well. 19 These data suggest that for inhibition, DAT agents with some elaboration at the β-position from the nitrogen atom such as a carbonyl oxygen seen both in the ester of methylphenidate and in the ketone of cathinones increase DAT inhibition but are not required for activity.…”

“…3,4-Dichlorobenzoylpiperidine 1b is a potent DAT reuptake inhibitor. 1 One goal of this study was to determine if the enhanced potency of 1b (IC 50 = 47 nM) 1 over 1a (IC 50 = 1080 nM) 1 is due to its lipophilic or electronic (e.g., hydrogen bonding or halogen bonding) character. If the former, dimethyl analogue 1c should be as potent as 1b at DAT.…”

“…The methyl group in the ester of 2 can also participate in hydrophobic interactions (i.e., VAL152 and ALA480, Table S1 and Figure S4) that might account for its 15-fold higher inhibitory potency than that of 1a (IC 50 = 72 and 1080 nM, respectively). 1 APP + inhibition assays at hSERT (Figure 4, Table 2) demonstrate the remarkable ability for substituents positioned at the aryl ring to influence transporter selectivity and potency. Compound 1d, with the extended π system due to a naphthyl ring, was ∼10-fold more potent at hSERT than the other compounds examined.…”