title: Structural Modification of the Designer Stimulant α-Pyrrolidinovalerophenone (α-PVP) Influences Potency at Dopamine Transporters.
abstract: 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 [(3)H]dopamine and [(3)H]serotonin in rat brain synaptosomes. None of the analogs significantly inhibited [(3)H]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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
authors.forename: R
authors.initials: R
authors.lastname: Kolanos
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
authors.forename: F
authors.initials: F
authors.lastname: Sakloth
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
authors.forename: A D
authors.initials: AD
authors.lastname: Jain
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: J S
authors.initials: JS
authors.lastname: Partilla
authors.affiliation: Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health , Baltimore, Maryland 21224, United States.
authors.forename: M H
authors.initials: MH
authors.lastname: Baumann
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University , 800 East Leigh Street, PO Box 980540, Richmond, Virginia 23298, United States.
authors.forename: R A
authors.initials: RA
authors.lastname: Glennon
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism*; D008297:Male; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D014316:Tritium / Q000378:metabolism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D011759:Pyrrolidines; D050486:Serotonin Plasma Membrane Transport Proteins; C542924:alpha-pyrrolidinovalerophenone; D014316:Tritium; D012701:Serotonin; D004298:Dopamine
keywords: DAT; SERT; Synthetic cathinones; dopamine transporter; flakka; serotonin transporter; α-PBP; α-PPP; α-PVP