Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

Niello, Marco; Sideromenos, Spyridon; Gradisch, R; O'Shea, Rosemarie; Schwazer, J; Sandtner, Walter; Maier, John G.; Jantsch, K.; Lupica, Carl R.; Hoffman, Alexander F.; Stockner, Thomas; Pollak, Daniela D.; Baumann, Michael H.; Sitte, Harald H.

doi:10.21203/rs.3.rs-612345/v1

Cited by 2 publications

(2 citation statements)

References 66 publications

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“…This is of great importance because the development of potential "anti-cocaine" medications has been focused on compounds capable of binding to DAT with high affinity, hindering cocaine-binding, while not displaying abuse potential [56,57]. Moreover, we cannot rule out the role/implication of the recently reported mechanism of action of α-PVP as a pseudo-irreversible non-competitive inhibition in the divergence observed between DAT affinity and DA uptake inhibition [58] as well as its relation in the development of novel "anti-cocaine" compounds. Therefore, the in vitro results obtained in the present study may help and be used as a starting point for the study and design of novel and potent DAT inhibitors but with clinical utility (i.e., without abuse potential), which warrants further investigation.…”

Section: Discussionmentioning

confidence: 91%

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

Nadal-Gratacós

Lleixà

Gibert-Serramià

et al. 2022

IJMS

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Changes in the molecular structure of synthetic cathinones has led to an increase in the number of novel emerging drugs in the illicit drug market at an unprecedented rate. Unfortunately, little is known about the neuropsychopharmacology of recently emerged halogen-substituted α-PVP derivatives. Thus, the aim of this study was to investigate the role of para- and meta-halogen (F-, Cl-, and Br-) substitutions on the in vitro, in silico, and in vivo effects of α-pyrrolidinopentiophenone (α-PVP) derivatives. HEK293 cells expressing the human dopamine or serotonin transporter (hDAT and hSERT) were used for the uptake inhibition and transporter affinity assays. Molecular docking was used to model the interaction mechanism against DAT. Swiss CD-1 mice were used for the horizontal locomotor activity, open field test, and conditioned place preference paradigm. All compounds demonstrated potent DA uptake inhibition and higher DAT selectivity than cocaine. Meta-substituted cathinones showed higher DAT/SERT ratios than their para- analogs, which correlates with an increased psychostimulant effect in vivo and with different meta- and para-in silico interactions at DAT. Moreover, all compounds induced rewarding and acute anxiogenic effects in mice. In conclusion, the present study demonstrates the role of meta- and para-halogen substitutions in the mechanism of action and provides the first evidence of the rewarding and anxiety-like properties of halogenated α-PVP derivatives.

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Section: Discussionmentioning

confidence: 91%

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

Nadal-Gratacós

Lleixà

Gibert-Serramià

et al. 2022

IJMS

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“…Thus, we examined pharmacodynamic properties of S-citalopram and R-citalopram, as well as S- and R-

-PVP. Generally, we saw no distinct enantioselective differences in uptake inhibition between the two compounds on any transporter, emphasizing the robustness of OCTs and PMAT concerning drug–transporter interactions, which discerns them from MATs [ 23 , 47 , 48 ].…”

Section: Discussionmentioning

confidence: 94%

Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter

Angenoorth

Stankovic

Niello

et al. 2021

IJMS

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Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.

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Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

Cited by 2 publications

References 66 publications

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

Neuropsychopharmacology of Emerging Drugs of Abuse: meta- and para-Halogen-Ring-Substituted α-PVP (“flakka”) Derivatives

Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1–3 and Human Plasma Membrane Monoamine Transporter

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