MDPV

MDPV acts as a potent norepinephrine–dopamine reuptake inhibitor (NDRI). Its 50“},”2”:{“wt”:”half-maximal inhibitory concentration”}},”i”:0}}]}”>half-maximal inhibitory concentration“}]]}”>IC₅₀Tooltip half-maximal inhibitory concentration for monoamine reuptake inhibition were 4.1 nM for dopamine, 26 nM for norepinephrine, and 3,349 nM for serotonin in rat brain synaptosomes. Similarly, MDPV’s half-maximal inhibitory concentration“}]],”parts”:[{“template”:{“target”:{“wt”:”Abbr”,”href”:”./Template:Abbr”},”params”:{“1”:{“wt”:”IC₅₀“},”2”:{“wt”:”half-maximal inhibitory concentration”}},”i”:0}}]}”>IC₅₀ values for monoamine reuptake inhibition were 10 nM for dopamine, 80 nM for norepinephrine, and 2,860 nM for serotonin in human embryonic kidney 293 (HEK293) cells expressing the monoamine transporters. Hence, its activity at the dopamine transporter is about six to eight times stronger than at the norepinephrine transporter and it is virtually inactive at the serotonin transporter. (S)-MDPV is the active enantiomer, whereas (R)-MDPV is far less potent.

MDPV is much more potent than amphetamine as an NDRI, with 23-fold higher potency for dopamine reuptake inhibition and 2.6-fold greater potency for norepinephrine reuptake inhibition in rat brain synaptosomes. With HEK293 cells expressing the monoamine transporters, Methylenedioxypyrovalerone was 568-fold more potent as a dopamine reuptake inhibitor and 12.5-fold more potent as a norepinephrine reuptake inhibitor than amphetamine. The drug is also far more potent as an NDRI than cocaine and mephedrone in both rat brain synaptosomes and HEK293 cells. Methylenedioxypyrovalerone is one of the most potent dopamine reuptake inhibitors in vitro or in vivo known. The only others that were more potent in vivo were desoxypipradrol (2-DPMP) and 3,4-dichloromethylphenidate (3-DCMP) and in vitro was α-PVP.

In addition to its monoamine reuptake inhibition, MDPV acts as a weakly efficacious partial norepinephrine–dopamine releasing agent (NDRA), with max“},”2”:{“wt”:”maximal efficacy”}},”i”:0}}]}”>maximal efficacy“}]]}”>E_maxTooltip maximal efficacy values of 24% for both norepinephrine and dopamine in rat brain synaptosomes. However, Methylenedioxypyrovalerone failed to produce any dopamine, norepinephrine, or serotonin release at a concentration of 100,000 nM in HEK293 cells.

Methylenedioxypyrovalerone has no record of FDA approved medical use. It has been shown to produce robust reinforcing effects and compulsive self-administration in rats, though this had already been provisionally established by a number of documented cases of misuse and addiction in humans before the animal tests were carried out. When assayed in mice, repeated exposure to Methylenedioxypyrovalerone causes not only an anxiogenic effect but also increased aggressive behaviour, a feature that has already been observed in humans. As with MDMA, Methylenedioxypyrovalerone also caused a faster adaptation to repeated social isolation in rodents. A cross-sensitization between MDPV and cocaine has been evidenced. Furthermore, both psychostimulants, MDPV and cocaine, restore drug-seeking behavior with respect to each other, although relapse into drug-taking is always more pronounced with the conditioning drug. Moreover, memories associated with MDPV require more time to be extinguished. Also, in MDPV-treated mice, a priming-dose of cocaine triggers significant neuroplasticity, implying a high vulnerability to its abuse.

Similarly to other dopamine reuptake inhibitors like methylphenidate and bupropion, Methylenedioxypyrovalerone has been found to block methamphetamine-induced dopamine release in vitro. This is thought to be because substrate-type monoamine releasing agents like amphetamine and methamphetamine enter monoaminergic neurons via the monoamine transporters and then induce monoamine efflux intracellularly. By blocking the dopamine transporter, it is thought to prevent access of these drugs into dopaminergic neurons and hence inhibits their dopamine release and associated effects.