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.

摘要: Novel psychoactive substances (NPS) may have unsuspected addiction potential through possessing stimulant properties. Stimulants normally act at the dopamine transporter (DAT) and thus increase (DA) availability in brain, including nucleus accumbens, within reward pathway. This paper aims to assess DAT responses dissociative diarylethylamine NPS by means of vitro silico approaches. We compared diphenidine (DPH) 2-methoxydiphenidine (methoxphenidine, 2-MXP/MXP) for their binding rat DAT, using autoradiography assessment [125I]RTI-121 displacement striatal sections. The drugs’ effects on electrically-evoked DA efflux were measured fast cyclic voltammetry accumbens slices. Computational modeling, molecular dynamics alchemical free energy simulations used analyse atomistic changes response each five dissociatives: DPH, 2-MXP, 3-MXP, 4-MXP 2-Cl-DPH, calculate relative energy. DPH increased as a result its whereas MXP had no significant effect either or evoked efflux. Our computational findings corroborate above explain conformational processes during interactions with NPS. suggest can addictive liability, unlike MXP, despite chemical similarities these two