Elucidating the Molecular Mechanism of Action of Stimulant New Psychoactive Substances (NPS) that target the High-affinity Transporter for Dopamine

Activity: Talk or presentation for an academic audienceInvited talk for an academic audience


Dr Michelle Sahai (University of Roehampton) Departmental Seminar "Elucidating the Molecular Mechanism of Action of Stimulant New Psychoactive Substances (NPS) that target the High-affinity Transporter for Dopamine."

Abstract: Drug misuse is a significant social and public health problem worldwide. Misused substances exert their neurobehavioural effects through changing neural signalling within the brain, many of them leading to substance dependence and addiction in the longer term. Among drugs with addictive liability, there are illicit classical stimulants such as cocaine and amphetamine, and their more recently available counterparts known as novel psychoactive substances (NPS). Stimulants normally increase dopamine availability in the brain, including the pathway implicated in reward-related behaviour. This pattern is observed in both animal and human brain. The main biological target of stimulants, both classical and NPS, is the dopamine transporter (DAT) implicated in the dopamine-enhancing effects of these drugs. To achieve a greater understanding of the core phenomena that decide about the addictive potential of stimulant NPS, studying the molecular mechanisms underpinning the interactions between stimulant NPS, such as benzofurans, cathinones or piperidine derivatives and DAT is critical. Towards this goal, we are currently taking advantage of powerful computational chemistry approaches such as molecular modelling and simulation in combination with standard neurobiological techniques such as autoradiography and voltammetry. The structural and pharmacological evidence of stimulant mechanism of action of different classes of NPS at DAT will be presented; evidence that suggests the potential addictive properties and informs about the health risk related to its use. Research of this kind is of interest to not only scientists but also health professionals as updated knowledge of NPS, their modes of action and health risks, is needed to tackle the challenges posed by NPS misuse. Currently applied to assess the addictive potential of NPS, this work provides further opportunities to understand the mechanisms of other physiologically important proteins, including the serotonin (SERT) and norepinephrine (NET) transporters. This work also highlights other targets of synthetic compounds like the serotonin, cannabinoid and opioid G protein-coupled receptors (GPCRs); the mechanism of the later should be urgently addressed considering the recent spate of opioid abuse.


Sahai, M. A. & Opacka-Juffry, J. Molecular mechanisms of action of stimulant novel psychoactive substances that target the high-affinity transporter for dopamine. Neuronal Signal. 5, 20210006 (2021).
Loi, B., Sahai, M. A., De Luca, M. A., Shiref, H. & Opacka-Juffry, J. The Role of Dopamine in the Stimulant Characteristics of Novel Psychoactive Substances (NPS) -Neurobiological and Computational Assessment Using the Case of Desoxypipradrol (2-DPMP). Front. Pharmacol. 11, 1 (2020).
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. 8, 63 (2018).
Sahai, M. A., Davidson, C., Khelashvili G., Barrese, V., Dutta, D., Weinstein, H. & Opacka-Juffry, J. Combined in vitro and in silico approaches to the assessment of stimulant properties of novel psychoactive substances – The case of the benzofuran 5-MAPB. Prog. Neuro-Psychopharmacology Biol. Psychiatry 75, 1–9 (2017).

Bio-sketch: Dr. Michelle Sahai is from Toronto, Canada. She completed her undergraduate and MSc degrees at the University of Toronto before moving to the UK, where she received her DPhil in Biochemistry from the Structural Bioinformatics and Computational Biochemistry Unit at the University of Oxford, under Professor(s) Phillip Biggin and Mark Sansom. After which she carried out postdoctoral research at the Department of Physiology and Biophysics, at the Weill Cornell Medical College, New York, NY under Professor Harel Weinstein. The formative experiences in these laboratories have fostered and consolidated her interest in the molecular mechanisms which underpin drug actions in biological systems. From 2014, Dr. Sahai was a Lecturer at the University of Roehampton, and Senior Lecturer since 2016. Her group at Roehampton focuses on answering important questions relating to membrane proteins and the structural, dynamic and electronic determinants of biological processes underlying physiological functions. Her current research involves computational studies on the interactions between new psychoactive substances (NPS, formerly ‘legal highs’) and their biological targets, specifically the dopamine transporter.

Estimated audience numbers (if applicable)

Period27 Jan 2023
Held atLancaster University, United Kingdom
Degree of RecognitionNational