ACS Chemical Neuroscience p. 1726 - 1731 (2015)
Update date:2022-08-03
Topics:
Kolanos
Sakloth
Jain
Partilla
Baumann
Glennon
α-Pyrrolidinovalerophenone (α-PVP, 7) is an illegal synthetic stimulant that is being sold on the clandestine market as flakka and gravel. The potent pharmacological effects of α-PVP are presumably mediated by inhibition of dopamine uptake at the dopamine transporter (DAT). However, little is known about how structural modification of α-PVP influences activity at DAT. Eleven analogs of α-PVP were synthesized and examined for their ability to inhibit uptake of [3H]dopamine and [3H]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [3H]serotonin uptake when tested at 10 μM at the serotonin transporter (SERT). All of the analogs behaved as DAT reuptake inhibitors, but potencies varied over a >1500-fold range. Potency was primarily associated with the nature of the α-substituent, with the more bulky substituents imparting the highest potency. Expansion of the pyrrolidine ring to a piperidine reduced potency up to 10-fold, whereas conformational constraint in the form of an aminotetralone resulted in the least potent compound. Our study provides the first systematic and comparative structure-activity investigation on the ability of α-PVP analogs to act as inhibitors of DAT.
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