Effects of the new psychoactive substances diclofensine, diphenidine, and methoxphenidine on monoaminergic systems
Dino Luethi, Marius C. Hoener, Matthias E. Liechti
European Journal of Pharmacology December 8, 2017 DOI: 10.1016/j.ejphar.2017.12.012 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro pharmacological profiling Peer reviewed |
|---|---|
| Population | Human embryonic kidney cells stably transfected with norepinephrine, dopamine, or serotonin transporters |
| Interventions | Diclofensine Diphenidine Methoxphenidine |
| Topics | Serotonin |
| Keywords | Monoaminergic Monoamine neurotransmitter Pharmacology Norepinephrine transporter Serotonin transporter Dopamine transporter 5-HT Receptor Endocrinology Biochemistry |
| Citations | 41 |
| Key points | Diclofensine potently inhibited all three monoamine transporters (2.5-4.8 μM) and bound to multiple receptors, while diphenidine and methoxphenidine showed more selective transporter inhibition and receptor binding profiles, and none of the drugs caused monoamine efflux. |
Abstract
Diclofensine, diphenidine, and methoxphenidine are new psychoactive substances (NPSs) that recently appeared on the illicit drug market. Pharmacological profiling of such newly emerged drugs is crucial for a better understanding of their psychotropic effects and toxicity. We therefore investigated the potential of these NPSs to inhibit the norepinephrine, dopamine, and serotonin transporters in human embryonic kidney cells stably transfected with the respective transporters. In addition, we determined monoamine transporter and receptor affinities for the substances. Diclofensine potently bound to the monoamine transporters in the submicromolar range and had similar inhibition potential for all three transporters in the range of 2.5-4.8μM. Moreover, diclofensine bound to adrenergic, dopamine, serotonin, and trace amine-associated receptors. Diphenidine was an equipotent inhibitor of the norepinephrine and dopamine transporters in the low micromolar range and a very weak inhibitor of the serotonin transporter. Besides binding to transporters, diphenidine bound to adrenergic α1A and α2A receptors and serotonin 5-hydroxytryptamine 1A (5-HT1A) and 5-HT2A receptors in the range of 4-11μM. Methoxphenidine bound to all transporters, but considerable inhibition (IC50 < 10μM) was observed only for the norepinephrine transporter. Moreover, methoxphenidine bound to adrenergic α2A and serotonin 5-HT2A and 5-HT2C receptors in the range of 2.5-8.2μM. None of the test drugs mediated substrate-type efflux of monoamines. These data demonstrate that the monoamine transporter inhibition and receptor interactions most likely mediate the psychoactive effects of diclofensine and possibly play a contributory role for diphenidine and methoxphenidine.
Comparable studies
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| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Neurotoxicity of the psychedelic amphetamine, methylenedioxymethamphetamine. Rats (implied by typical neurochemical study context) | 1987 | Experimental study | |
| Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors In vitro and in vivo (rodent) models | 2023 | Experimental study | |
| 3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites. Rat brain | 1987 | Animal experiment | |
| Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs Human and mouse dopamine, norepinephrine, and serotonin transporters expressed in cells | 2006 | In vitro laboratory study |
Citations in the library
Cited by 14
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- New psychoactive substances (NPS) and serotonin syndrome onset: A systematic review. Experimental Neurology May 1, 2021
- Molecular and clinical aspects of potential neurotoxicity induced by new psychoactive stimulants and psychedelics Experimental Neurology June 4, 2021
- Intriguing Cytotoxicity of the Street Dissociative Anesthetic Methoxphenidine: Unexpected Impurities Spotted International Journal of Molecular Sciences February 14, 2022
- A structural spectroscopic study of dissociative anaesthetic methoxphenidine New Journal of Chemistry 2023
and 9 more in the library
Cites 17
- Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Neuroreport December 1, 1998
- Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology May 20, 2016
- From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Testing and Analysis 2014
- Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology December 1, 2015
- Duloxetine Inhibits Effects of MDMA (“Ecstasy") In Vitro and in Humans in a Randomized Placebo-Controlled Laboratory Study PLoS One May 4, 2012
and 12 more in the library