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Brain Sci. 2018, 8(4), 63; https://doi.org/10.3390/brainsci8040063

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

1
Department of Life Sciences, University of Roehampton, London SW15 4JD, UK
2
St George’s, University of London, London SW17 0RE, UK
3
Pharmacy & Biomedical Sciences, University of Central Lancashire, Preston PR1 2HE, UK
*
Author to whom correspondence should be addressed.
Received: 2 February 2018 / Revised: 21 March 2018 / Accepted: 22 March 2018 / Published: 7 April 2018
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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. View Full-Text
Keywords: dopamine; DAT; brain; addiction; molecular dynamics; free energy calculation; autoradiography; voltammetry; diphenidine dopamine; DAT; brain; addiction; molecular dynamics; free energy calculation; autoradiography; voltammetry; diphenidine
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Sahai, M.A.; Davidson, C.; Dutta, N.; Opacka-Juffry, J. 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. Brain Sci. 2018, 8, 63.

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