benzofurans and pentedrone

New psychoactive substances (NPSs), including substituted cathinones and other stimulants, are synthesized, sold on the Internet, and ingested without knowledge of their pharmacological activity and/or toxicity. In vitro pharmacology plays a role in therapeutic drug development, drug-protein in silico interaction modeling, and drug scheduling.. The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability.. Affinities to displace the radioligand [. Most α-pyrrolidinophenones had high hDAT potencies and selectivities in uptake assays, with hDAT/hSERT uptake selectivity ratios of 83-360. Other substituted cathinones varied in their potencies and selectivities, with N-ethyl-hexedrone and N-ethyl-pentylone having highest hDAT potencies and N-propyl-pentedrone having highest hDAT selectivity. 4-Cl-ethcathinone and 3,4-methylenedioxy-N-propylcathinone had higher hSERT selectivity. Benzofurans generally had low hDAT selectivity, especially 1-(2,3-dihydrobenzofuran-5-yl)-N-methylpropan-2-amine, with 25-fold higher hSERT potency. Consistent with this selectivity, the benzofurans were releasers at hSERT. Modeling indicated key amino acids in the transporters' binding pockets that influence drug affinities.. The α-pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.

Topics: Alkaloids; Benzofurans; Central Nervous System Stimulants; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dose-Response Relationship, Drug; HEK293 Cells; Humans; Methylamines; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins; Pentanones; Protein Structure, Secondary; Protein Structure, Tertiary; Serotonin; Serotonin Plasma Membrane Transport Proteins; Structure-Activity Relationship; Vesicular Biogenic Amine Transport Proteins