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

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.

How preclinical studies have influenced novel psychoactive substance legislation in the UK and Europe

“…modelling the effects of the drugs at receptors or transporters of interest. We have done this for some ketamine‐like NPS including diphenidine, methoxphenidine, MDMA, and some similar NPS including 5‐APB and 5‐MAPB . We also suggest that future studies focus more on measures of toxicity (e.g.…”

“…We have done this for some ketamine-like NPS including diphenidine, methoxphenidine, MDMA, and some similar NPS including 5-APB and 5-MAPB. 84,140 We also suggest that future studies focus more on measures of toxicity (e.g. neurotoxicity, vasoconstriction, hepatotoxicity, seizures and hyperthermia) as this has clearly been overlooked with most studies focussing on rodent behavioural or neurochemical (dopamine) measures of dependence.…”

“…Some researchers have gone a step further, using in silico studies to predict addictive liability of NPS. The benzofurans 5‐APB and 5‐MAPB were predicted to bind to DAT in a similar way to MDMA, while ketamine‐like NPS diphenidine and methoxphenidine were predicted to bind differently at DAT …”

“…while ketamine-like NPS diphenidine and methoxphenidine were predicted to bind differently at DAT 140. EVIDENCE USED IN UK LEGISLATION AND IN EUROPE Evidence used in the UKIn the UK, the government takes advice on issues around drugs of abuse from the ACMD who risk assess emerging substances and issue subsequent recommendations.141 The ACMD also advises the government on the control of drugs and drugs requiring a temporary class drug order.…”

The Role of Dopamine in the Stimulant Characteristics of Novel Psychoactive Substances (NPS)—Neurobiological and Computational Assessment Using the Case of Desoxypipradrol (2-DPMP)

“…methoxyphenidine (Wallach et al, 2016;Luethi et al, 2018;Sahai et al, 2018). We have characterized those stimulants by means of neurobiological in vitro methods, and in silico, using molecular modeling of interactions between the drugs and DAT (Sahai et al, 2017;Sahai et al, 2018). We have also predicted their respective prodopaminergic properties without in vivo evidence of dopamine release caused by those stimulants.…”