Neuropharmacology of 3,4-Methylenedioxypyrovalerone (MDPV), Its Metabolites, and Related Analogs

Abstract

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.

The clinical challenges of synthetic cathinones

“…They are non-substrate transporter inhibitors, showing inhibitory potencies at NE transporter and DAT methylamphetamine 13 or cocaine. 14,15 MDPV and α-PVP are both considered to be cocaine-like, whilst being more effective reinforcers. 16 Recent research on the pyrovalerone analogue α-pyrrolidinopentiothiophenone (α-PVT) suggests it has reinforcing and rewarding effects similar to those of both methylamphetamine and cocaine.…”

“…17 It has been suggested that the reinforcing properties of cathinone stimulants are positively correlated with their selectivity for the dopamine (DAT) relative to SERT. 15,[18][19][20] What is already known about this subject • NPSfinder ® has identified some 41 cathinone molecules not known to either the UNODC or EMCDDA.…”

“…They promote the release of NE and DA in a similar way to methylamphetamine; Pyrovalerone‐like effects; associated with: pyrovalerone, methylenedioxypyrovalerone (MDPV) and α‐pyrrolidinovalerophenone (α‐PVP). They are non‐substrate transporter inhibitors, showing inhibitory potencies at NE transporter and DAT ≥ methylamphetamine or cocaine . MDPV and α‐PVP are both considered to be cocaine‐like, whilst being more effective reinforcers .…”

“…It has been suggested that the reinforcing properties of cathinone stimulants are positively correlated with their selectivity for the dopamine (DAT) relative to SERT …”

Simultaneous determination of N‐ethylpentylone, dopamine, 5‐hydroxytryptamine and their metabolites in rat brain microdialysis by liquid chromatography tandem mass spectrometry

“…A large number of studies have shown that the stimulation of synthetic cathinones is closely related to changes in neurotransmitters such as dopamine (DA) serotonin (5‐HT) and their metabolites 3,4‐dihydroxyphenylacetic acid (DOPAC), 3‐methoxytyramine (3‐MT) and 5‐hydroxyindole‐3‐acetic acid (5‐HIAA) in the brain (Baumann et al, ; Baumann et al, ; Baumann, Partilla, & Lehner, ; De Felice, Glennon, & Negus, ; Lopez‐Arnau et al, ; Lopez‐Arnau, Martinez‐Clemente, Pubill, Escubedo, & Camarasa, ; Martinez‐Clemente, Escubedo, Pubill, & Camarasa, ; Marusich, Gay, & Blough, ; Simmler et al, ). Therefore, studying the changes in NEP, DA, 5‐HT, DOPAC, 3‐MT and 5‐HIAA concentration will help us understand the effects of NEP on dopaminergic and serotonergic systems.…”