Functional characterization of N-octyl 4-methylamphetamine variants and related bivalent compounds at the dopamine and serotonin transporters using Ca2+ channels as sensors
| Autor: | Richard A. Glennon, Iwona Ruchala, Jose M. Eltit, Rita Yu-Tzu Chen, Vy T. Nguyen, Umberto Maria Battisti |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Pharmacology Drug discovery Transporter Toxicology 4-Methylamphetamine 03 medical and health sciences chemistry.chemical_compound 030104 developmental biology 0302 clinical medicine Monoamine neurotransmitter Biochemistry chemistry Dopamine 030220 oncology & carcinogenesis medicine Serotonin Amphetamine Reuptake inhibitor medicine.drug |
| Zdroj: | Toxicology and Applied Pharmacology. 419:115513 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2021.115513 |
| Popis: | The early characterization of ligands at the dopamine and serotonin transporters, DAT and SERT, respectively, is important for drug discovery, forensic sciences, and drug abuse research. 4-Methyl amphetamine (4-MA) is a good example of an abused drug whose overdose can be fatal. It is a potent substrate at DAT and SERT where its simplest secondary amine (N-methyl 4-MA) retains substrate activity at them. In contrast, N-n-butyl 4-MA is very weak, therefore it was categorized as inactive at these transporters. Here, N-octyl 4-MA and other related compounds were synthesized, and their activities were evaluated at DAT and SERT. To expedite this endeavor, cells expressing DAT or SERT were co-transfected with a voltage-gated Ca2+ channel and, the genetically-encoded Ca2+ sensor, GCaMP6s. Control compounds and the newly synthesized molecules were tested on these cells using an automated multi-well fluorescence plate reader; substrates and inhibitors were identified successfully at DAT and SERT. N-Octyl 4-MA and three bivalent compounds were inhibitors at these transporters. These findings were validated by measuring Ca2+-mobilization using quantitative fluorescence microscopy. The bivalent molecules were the most potent of the series and were further characterized in an uptake-inhibition assay. Compared to cocaine, they showed comparable potency inhibiting uptake at DAT and higher potency at SERT. These observations support a previous hypothesis that amphetamine-related (and, here, N-extended alkyl and) bivalent arylalkylamine molecules are active at monoamine transporters, showing potent activity as reuptake inhibitors, and implicate the involvement of a distant auxiliary binding feature to account for their actions at DAT and SERT. |
| Databáze: | OpenAIRE |
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