N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
Ernesto SolisMichael H Baumann

Abstract

Clandestine chemists synthesize novel stimulant drugs by exploiting structural templates known to target monoamine transporters for dopamine, norepinephrine, and serotonin (DAT, NET, and SERT, respectively). 4-Methylamphetamine (4-MA) is an emerging drug of abuse that interacts with transporters, but limited structure-activity data are available for its analogs. Here we employed uptake and release assays in rat brain synaptosomes, voltage-clamp current measurements in cells expressing transporters, and calcium flux assays in cells coexpressing transporters and calcium channels to study the effects of increasing N-alkyl chain length of 4-MA on interactions at DAT, NET, and SERT. In addition, we performed intracranial self-stimulation in rats to understand how the chemical modifications affect abuse liability. All 4-MA analogs inhibited uptake at DAT, NET, and SERT, but lengthening the amine substituent from methyl to ethyl, propyl, and butyl produced a stepwise decrease in potency. N-methyl 4-MA was an efficacious substrate-type releaser at DAT that evoked an inward depolarizing current and calcium influx, whereas other analogs did not exhibit these effects. N-methyl and N-ethyl 4-MA were substrates at NET, whereas N-propyl and ...Continue Reading

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Citations

Aug 29, 2018·The Journal of Pharmacology and Experimental Therapeutics·Megan J MoerkeS Stevens Negus
Mar 23, 2019·The Journal of Pharmacology and Experimental Therapeutics·Charles W SchindlerMichael H Baumann
Jun 17, 2020·Journal of Psychopharmacology·Michael B Gatch, Michael J Forster
Oct 22, 2020·The Journal of Pharmacology and Experimental Therapeutics·Charles W SchindlerMichael H Baumann
Mar 11, 2021·ACS Chemical Neuroscience·Grant C GlatfelterMichael H Baumann
Oct 3, 2018·ACS Chemical Neuroscience·Julian MaierHarald H Sitte

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