Mechanistic Insights into the Stimulant Properties of Novel Psychoactive Substances (NPS) and Their Discrimination by the Dopamine Transporter-In Silico and In Vitro Exploration of Dissociative Diarylethylamines.
Michelle A Sahai, Colin Davidson, Neelakshi Dutta, Jolanta Opacka-Juffry
Brain Sciences April 7, 2018 DOI: 10.3390/brainsci8040063 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vitro and in silico study Peer reviewed |
|---|---|
| Population | Rat striatal sections and accumbens slices |
| Interventions | Diphenidine 2-methoxydiphenidine |
| Topics | Addiction |
| Keywords | Dat Autoradiography Brain Diphenidine Dopamine Free energy calculation Molecular dynamics Voltammetry |
| Key points | Diphenidine increases dopamine efflux by binding to the dopamine transporter, whereas methoxphenidine has no significant effect on dopamine transporter binding or evoked dopamine release. |
Abstract
Novel psychoactive substances (NPS) may have unsuspected addiction potential through possessing stimulant properties. Stimulants normally act at the dopamine transporter (DAT) and thus increase dopamine (DA) availability in the brain, including nucleus accumbens, within the reward and addiction pathway. This paper aims to assess DAT responses to dissociative diarylethylamine NPS by means of in vitro and in silico approaches. We compared diphenidine (DPH) and 2-methoxydiphenidine (methoxphenidine, 2-MXP/MXP) for their binding to rat DAT, using autoradiography assessment of [125I]RTI-121 displacement in rat striatal sections. The drugs' effects on electrically-evoked DA efflux were measured by means of fast cyclic voltammetry in rat accumbens slices. Computational modeling, molecular dynamics and alchemical free energy simulations were used to analyse the atomistic changes within DAT in response to each of the five dissociatives: DPH, 2-MXP, 3-MXP, 4-MXP and 2-Cl-DPH, and to calculate their relative binding free energy. DPH increased DA efflux as a result of its binding to DAT, whereas MXP had no significant effect on either DAT binding or evoked DA efflux. Our computational findings corroborate the above and explain the conformational responses and atomistic processes within DAT during its interactions with the dissociative NPS. We suggest DPH can have addictive liability, unlike MXP, despite the chemical similarities of these two NPS.
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| Effects of ibogaine on acute signs of morphine withdrawal in rats: independence from tremor. Morphine-dependent rats | 1992 | Randomized controlled trial | |
| Structure-based discovery of conformationally selective inhibitors of the serotonin transporter. Mice | 2023 | Computational docking and experimental validation | |
| Reinforcing Effects of MDMA (‘Ecstasy’) in Drug-Naive and Cocaine-Trained Rats Rats | 2001 | Experimental study |
Citations in the library
Cited by 6
- A structural spectroscopic study of dissociative anaesthetic methoxphenidine New Journal of Chemistry 2023
- Rewarding and reinforcing effects of two dissociative-based new psychoactive substances, deschloroketamine and diphenidine, in mice. Pharmacology, Biochemistry, and Behavior February 1, 2022
- Deaths related to the use of diarylethylamines, with a focus on the United Kingdom: A systematic review and case series report. Journal of Psychopharmacology July 1, 2025
- Effects of 4-position substitutions of diphenidine on blood-brain barrier penetration and dopamine release in the nucleus accumbens of rats. Forensic Toxicology July 1, 2026
- Synthesis and crystal structures of five fluorinated diphenidine derivatives. Acta Crystallographica. Section E, Crystallographic Communications March 1, 2025
and 1 more in the library
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