Structure-activity relationships of bath salt components: substituted cathinones and benzofurans at biogenic amine transporters
| Autor: | Tracy L. Swanson, Shanthi Nagarajan, Katherine M. Wolfrum, John F. Reed, Aaron Nilsen, Aaron Janowsky, Amy J. Eshleman |
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| Rok vydání: | 2018 |
| Předmět: |
Serotonin
Neurotransmitter uptake Stereochemistry medicine.medical_treatment Dopamine Protein Structure Secondary Article 03 medical and health sciences Methylamines Norepinephrine Structure-Activity Relationship 0302 clinical medicine Alkaloids Biogenic amine Pentanones Vesicular Biogenic Amine Transport Proteins medicine Radioligand Humans Benzofurans Pharmacology chemistry.chemical_classification Serotonin Plasma Membrane Transport Proteins Dopamine Plasma Membrane Transport Proteins Norepinephrine Plasma Membrane Transport Proteins Dose-Response Relationship Drug Biological activity Transporter 030227 psychiatry Amino acid Protein Structure Tertiary Stimulant HEK293 Cells chemistry Central Nervous System Stimulants 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Psychopharmacology. 236(3) |
| ISSN: | 1432-2072 |
| Popis: | 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 [125I]RTI-55 and potencies to inhibit [3H]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 [3H]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters. 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. |
| Databáze: | OpenAIRE |
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