Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs.
3,4-Methylenedioxypyrovalerone (MDPV) is a psychoactive component of so-called bath salts products that has caused serious medical consequences in humans. In this chapter, we review the neuropharmacology of MDPV and related analogs, and supplement the discussion with new results from our preclinical experiments. MDPV acts as a potent uptake inhibitor at plasma membrane transporters for dopamine (DAT) and norepinephrine (NET) in nervous tissue. The MDPV formulation in bath salts is a racemic mixture, and the S isomer is much more potent than the R isomer at blocking DAT and producing abuse-related effects. Elevations in brain extracellular dopamine produced by MDPV are likely to underlie its locomotor stimulant and addictive properties. MDPV displays rapid pharmacokinetics when injected into rats (0.5-2.0 mg/kg), with peak plasma concentrations achieved by 10-20 min and declining quickly thereafter. MDPV is metabolized to 3,4-dihydroxypyrovalerone (3,4-catechol-PV) and 4-hydroxy-3-methoxypyrovalerone (4-OH-3-MeO-PV) in vivo, but motor activation produced by the drug is positively correlated with plasma concentrations of parent drug and not its metabolites. 3,4-Catechol-PV is a potent uptake blocker at DAT in vitro but has little activity after administration in vivo. 4-OH-3-MeO-PV is the main MDPV metabolite but is weak at DAT and NET. MDPV analogs, such as α-pyrrolidinovalerophenone (α-PVP), display similar ability to inhibit DAT and increase extracellular dopamine concentrations. Taken together, these findings demonstrate that MDPV and its analogs represent a unique class of transporter inhibitors with a high propensity for abuse and addiction.
Designer Drug Research Unit of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA. mbaumann@mail.nih.gov.
Michael H
MH
Baumann
Designer Drug Research Unit of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA.
Mohammad O
MO
Bukhari
Designer Drug Research Unit of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA.
Kurt R
KR
Lehner
Chemistry and Drug Metabolism Section of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA.
Sebastien
S
Anizan
Drug Design and Synthesis Section of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA.
Kenner C
KC
Rice
Chemistry and Drug Metabolism Section of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA.|Department of Sciences, John Jay College of Criminal Justice, City University of New York, New York, NY, USA.
Marta
M
Concheiro
Chemistry and Drug Metabolism Section of the Intramural Research Program, National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA.
Marilyn A
MA
Huestis
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D006801:Humans; D009480:Neuropharmacology; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000187:drug effects*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D019966:Substance-Related Disorders; D000094982:Synthetic Cathinone
D018759:Adrenergic Uptake Inhibitors; D052117:Benzodioxoles; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011619:Psychotropic Drugs; D011759:Pyrrolidines; C542924:alpha-pyrrolidinovalerophenone; D000094982:Synthetic Cathinone
Addiction; Dopamine; MDPV; Pyrrolidinophenones; Synthetic cathinones; Transporter; Uptake; α-PVP