Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters

• Published in: Psychopharmacology 2019-03, Vol.236 (3), p.939-952
• Main Authors: Eshleman, Amy J., Nagarajan, Shanthi, Wolfrum, Katherine M., Reed, John F., Swanson, Tracy L., Nilsen, Aaron, Janowsky, Aaron
• Format: Article
• Language: English
• Subjects: Alkaloids - chemistry; Alkaloids - metabolism; Amines; Amino acids; Bath products; Benzofurans - chemistry; Benzofurans - metabolism; Biogenic amines; Biomedical and Life Sciences; Biomedicine; Carbon; Catecholamines; Central Nervous System Stimulants - chemistry; Central Nervous System Stimulants - metabolism; Central Nervous System Stimulants - pharmacology; Cocaine; Computational neuroscience; Computer simulation; Dopamine; Dopamine - metabolism; Dopamine Plasma Membrane Transport Proteins - metabolism; Dopamine transporter; Dose-Response Relationship, Drug; Drug abuse; Drug development; Drug interactions; Ecstasy; Ecstasy (Drug); Health aspects; HEK293 Cells; Humans; Interaction models; Kidneys; Legal liability; Liability; Methamphetamine; Methylamines - metabolism; Neurosciences; Neurotransmitter release; Norepinephrine; Norepinephrine - metabolism; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Original Investigation; Pentanones - metabolism; Pharmacology; Pharmacology/Toxicology; Phenols (Class of compounds); Protein Structure, Secondary; Protein Structure, Tertiary; Psychiatry; Psychopharmacology; Resveratrol; Selectivity; Serotonin; Serotonin - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; Stimulants; Structure-Activity Relationship; Structure-activity relationships; Toxicity; Vesicular Biogenic Amine Transport Proteins
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-018-5059-5

Rationale 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. Objectives The goal of this research was to determine mechanisms of action that may indicate NPS abuse liability. Methods Affinities to displace the radioligand [ 125 I]RTI-55 and potencies to inhibit [ 3 H]neurotransmitter uptake for 22 cathinones, 6 benzofurans and another stimulant were characterized using human embryonic kidney cells stably expressing recombinant human transporters for dopamine, norepinephrine, or serotonin (hDAT, hNET, or hSERT, respectively). Selected compounds were tested for potencies and efficacies at inducing [ 3 H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. Results 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. Conclusions 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.