N-Alkylated Analogs of 4-Methylamphetamine (4-MA) Differentially Affect Monoamine Transporters and Abuse Liability
| Autor: | Michael H. Baumann, John S. Partilla, S. Stevens Negus, Farhana Sakloth, Ernesto Solis, Kathryn L. Schwienteck, Iwona Ruchala, Louis J. De Felice, Richard A. Glennon, Jose M. Eltit |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine Serotonin Alkylation Dopamine Amphetamine-Related Disorders Pharmacology Membrane Potentials Rats Sprague-Dawley 4-Methylamphetamine Norepinephrine Xenopus laevis 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine In vivo Membrane Transport Modulators Calcium flux medicine Animals Humans Voltage-dependent calcium channel Chemistry Amphetamines Brain Transporter Psychiatry and Mental health HEK293 Cells 030104 developmental biology Monoamine neurotransmitter Biochemistry Vesicular Monoamine Transport Proteins Oocytes Original Article Calcium Calcium Channels 030217 neurology & neurosurgery Synaptosomes medicine.drug |
| Zdroj: | Neuropsychopharmacology. 42:1950-1961 |
| ISSN: | 1740-634X 0893-133X |
| DOI: | 10.1038/npp.2017.98 |
| Popis: | 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 N-butyl 4-MA were not. All analogs acted as SERT substrates, though N-butyl 4-MA had very weak effects. Intracranial self-stimulation in rats showed that elongating the N-alkyl chain decreased abuse-related effects in vivo that appeared to parallel reductions in DAT activity. Overall, converging lines of evidence show that lengthening the N-alkyl substituent of 4-MA reduces potency to inhibit transporters, eliminates substrate activity at DAT and NET, and decreases abuse liability of the compounds. |
| Databáze: | OpenAIRE |
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