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Interaction profiles of central nervous system active drugs at human organic cation transporters 1-3 and human plasma membrane monoamine transporter

Angenoorth, TJF, Stankovic, S, Niello, N, Holy, M, Brandt, SD, Sitte, HH and Maier, J (2021) Interaction profiles of central nervous system active drugs at human organic cation transporters 1-3 and human plasma membrane monoamine transporter. International Journal of Molecular Sciences, 22 (23). ISSN 1422-0067

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Many psychoactive compounds have been shown to primarily interact with high-affinity and low-capacity solute carrier 6 (SLC6) monoamine transporters for norepinephrine (NET; norepinephrine transporter), dopamine (DAT; dopamine transporter) and serotonin (SERT; serotonin transporter). Previous studies indicate an overlap between the inhibitory capacities of substances at SLC6 and SLC22 human organic cation transporters (SLC22A1–3; hOCT1–3) and the human plasma membrane monoamine transporter (SLC29A4; hPMAT), which can be classified as high-capacity, low-affinity monoamine transporters. However, interactions between central nervous system active substances, the OCTs, and the functionally-related PMAT have largely been understudied. Herein, we report data from 17 psychoactive substances interacting with the SLC6 monoamine transporters, concerning their potential to interact with the human OCT isoforms and hPMAT by utilizing radiotracer-based in vitro uptake inhibition assays at stably expressing human embryonic kidney 293 cells (HEK293) cells. Many compounds inhibit substrate uptake by hOCT1 and hOCT2 in the low micromolar range, whereas only a few substances interact with hOCT3 and hPMAT. Interestingly, methylphenidate and ketamine selectively interact with hOCT1 or hOCT2, respectively. Additionally, 3,4-methylenedioxymethamphetamine (MDMA) is a potent inhibitor of hOCT1 and 2 and hPMAT. Enantiospecific differences of R- and S-α-pyrrolidinovalerophenone (R- and S-α-PVP) and R- and S-citalopram and the effects of aromatic substituents are explored. Our results highlight the significance of investigating drug interactions with hOCTs and hPMAT, due to their role in regulating monoamine concentrations and xenobiotic clearance.

Item Type: Article
Uncontrolled Keywords: 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences
Subjects: Q Science > QD Chemistry
Q Science > QH Natural history > QH301 Biology
Q Science > QH Natural history > QH426 Genetics
R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: MDPI AG
Date Deposited: 01 Dec 2021 12:13
Last Modified: 01 Dec 2021 12:13
DOI or ID number: 10.3390/ijms222312995
URI: https://researchonline.ljmu.ac.uk/id/eprint/15854
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