期刊
PSYCHOPHARMACOLOGY
卷 236, 期 3, 页码 939-952出版社
SPRINGER
DOI: 10.1007/s00213-018-5059-5
关键词
New psychoactive substances; Psychostimulant; Pharmacology; Transporter; Benzofurans; Cathinones
资金
- Department of Justice Drug Enforcement Administration [D-15-OD-0002]
- Veterans Affairs Merit Review program [I01BX002758]
- Career Scientist program [14S-RCS-006]
- Methamphetamine Abuse Research Center [P50 DA018165]
- National Institutes of Health/National Institute on Drug Abuse [ADA12013]
RationaleNew 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.ObjectivesThe goal of this research was to determine mechanisms of action that may indicate NPS abuse liability.MethodsAffinities to displace the radioligand [I-125]RTI-55 and potencies to inhibit [H-3]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 [H-3]neurotransmitter release via the transporters. Computational modeling was conducted to explain plausible molecular interactions established by NPS and transporters.ResultsMost -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.ConclusionsThe -pyrrolidinophenones, with high hDAT selectivity, have high abuse potential. Lower hDAT selectivity among benzofurans suggests similarity to methylenedioxymethamphetamine, entactogens with lower stimulant activity.
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