The new stimulant designer compound pentedrone exhibits rewarding properties and affects dopaminergic activity

Hwang, Ji-Young; Kim, Jun-Sub; Oh, Jae-Hyuk; Hong, Sa-Ik; Ma, Shi-Xun; Jung, Younghun; Lee, Seok‐Yong; Kim, Hyoung‐Chun; Jang, Choon‐Gon

doi:10.1111/adb.12299

Cited by 16 publications

(19 citation statements)

References 43 publications

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“…They produce long-lasting locomotor stimulant effects and fully substitute for discriminative stimulus effects of both cocaine and METH, and pentedrone increases conditioned place preference in mice and is self-administered by rats (Gatch et al, 2015b;Hwang et al, 2015). Both compounds may have abuse potential.…”

Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Eshleman

Wolfrum

Reed

et al. 2016

J Pharmacol Exp Ther

115

187

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Synthetic cathinones are components of "bath salts" and have physical and psychologic side effects, including hypertension, paranoia, and hallucinations. Here, we report interactions of 20 "bath salt" components with human dopamine, serotonin, and norepinephrine transporters [human dopamine transporter (hDAT), human serotonin transporter (hSERT), and human norepinephrine transporter (hNET), respectively] heterologously expressed in human embryonic kidney 293 cells. Transporter inhibitors had nanomolar to micromolar affinities (K i values) at radioligand binding sites, with relative affinities of hDAT.hNET.hSERT for a-pyrrolidinopropiophenone (a-PPP), a-pyrrolidinobutiophenone, a-pyrrolidinohexiophenone, 1-phenyl-2-(1-pyrrolidinyl)-1-heptanone, 3,4-methylenedioxy-a-pyrrolidinopropiophenone, 3,4-methylenedioxy-a-pyrrolidinobutiophenone, 4-methyl-a-pyrrolidinopropiophenone, a-pyrrolidinovalerophenone, 4-methoxy-a-pyrrolidinovalerophenone, a-pyrrolidinopentiothiophenone (alpha-PVT), and a-methylaminovalerophenone, and hDAT.hSERT.hNET for methylenedioxypentedrone. Increasing the a-carbon chain length increased the affinity and potency of the a-pyrrolidinophenones. Uptake inhibitors had relative potencies of hDAT.hNET.hSERT except a-PPP and a-PVT, which had highest potencies at hNET. They did not induce [3 H]neurotransmitter release. Substrates can enter presynaptic neurons via transporters, and the substrates methamphetamine and 3,4-methylenedioxymethylamphetamine are neurotoxic. We determined that 3-fluoro-, 4-bromo-, 4-chloromethcathinone, and 4-fluoroamphetamine were substrates at all three transporters; 5,6-methylenedioxy-2-aminoindane (MDAI) and 4-methylethcathinone (4-MEC) were substrates primarily at hSERT and hNET; and 3,4-methylenedioxy-Nethylcathinone (ethylone) and 5-methoxy-methylone were substrates only at hSERT and induced [ 3 H]neurotransmitter release. Significant correlations between potencies for inhibition of uptake and for inducing release were observed for these and additional substrates. The excellent correlation of efficacy at stimulating release versus K i /IC 50 ratios suggested thresholds of binding/uptake ratios above which compounds were likely to be substrates. Based on their potencies at hDAT, most of these compounds have potential for abuse and addiction. 4-Bromomethcathinone, 4-MEC, 5-methoxy-methylone, ethylone, and MDAI, which have higher potencies at hSERT than hDAT, may have empathogen psychoactivity.

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Section: Discussionmentioning

confidence: 99%

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Eshleman

Wolfrum

Reed

et al. 2016

J Pharmacol Exp Ther

115

187

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“…Although prior preclinical evidence is not comprehensive, there is evidence that pentedrone increases locomotor activity in mice (Gatch et al, 2015;Hwang et al, 2017), supports intravenous self-administration (IVSA) in male Wistar rats (Hwang et al, 2017) and substitutes for the discriminative stimulus effect of methamphetamine and cocaine in male rats (Gatch et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Locomotor and Reinforcing Effects of Pentedrone, Pentylone and Methylone in Rats

Javadi‐Paydar

Nguyen

Vandewater

et al. 2017

Preprint

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The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the α-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for α-PVP and α-pyrrolidinohexiophenone (α-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 °C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 °C) was observed for four hours after 10 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than α-PVP or α-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone.peer-reviewed)

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“…Although prior preclinical evidence is not comprehensive, there is evidence that pentedrone increases locomotor activity in mice (Gatch et al , 2015; Hwang et al , 2017), supports intravenous self-administration (IVSA) in male Wistar rats (Hwang et al , 2017) and substitutes for the discriminative stimulus effect of methamphetamine and cocaine in male rats (Gatch et al , 2015). Pentylone likewise increases locomotor activity in mice and substitutes for methamphetamine and cocaine (Gatch et al , 2015).…”

Section: Introductionmentioning

confidence: 99%

Locomotor and reinforcing effects of pentedrone, pentylone and methylone in rats

et al. 2018

View full text Add to dashboard Cite

The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the α-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for α-PVP and α-pyrrolidinohexiophenone (α-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 °C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 °C) was observed for four hours after 10.0 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than α-PVP or α-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone. This article is part of the Special Issue entitled 'Designer Drugs and Legal Highs.'

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The new stimulant designer compound pentedrone exhibits rewarding properties and affects dopaminergic activity

Cited by 16 publications

References 43 publications

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Structure-Activity Relationships of Substituted Cathinones, with Transporter Binding, Uptake, and Release

Locomotor and Reinforcing Effects of Pentedrone, Pentylone and Methylone in Rats

Locomotor and reinforcing effects of pentedrone, pentylone and methylone in rats

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