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

2-(Benzoyl)piperidines (analogues of 1a), structural hybrids of the clinically employed ADHD medication methylphenidate (2) and the abused synthetic cathinone pentedrone (3), have been previously reported to act as novel and selective reuptake inhibitors of the human dopamine transporter (hDAT). One of the more potent benzoylpiperidines, as is the case with methylphenidate analogues, is its 3,4-dichloroaryl counterpart. Here, we demonstrate using homology models that these compounds (i.e., benzoylpiperidines and methylphenidate analogues) likely bind in a comparable manner at hDAT. In addition, it is shown here that the 3,4-dichlorobenzoylpiperidine analogue of 1a is more potent than its 3,4-dimethyl counterpart, suggesting that the electronic character of the substituents might play a role in the potency of these hybrids. Furthermore, the 3,4-benz-fused (i.e., naphthyl) benzoylpiperidine analogue acts in the same manner as its corresponding methylphenidate counterpart at hDAT. As with its methylphenidate counterpart, the naphthyl compound also acts, rather uniquely (although with lower potency) relative to other members of the two series, at the human serotonin transporter (hSERT). In conclusion, the benzoylpiperidines represent a novel structural class of hDAT reuptake inhibitors that function in a manner similar to their methylphenidate counterparts.