PMID- 34884800 OWN - NLM STAT- MEDLINE DCOM- 20211220 LR - 20220727 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 23 DP - 2021 Nov 30 TI - Interaction Profiles of Central Nervous System Active Drugs at Human Organic Cation Transporters 1-3 and Human Plasma Membrane Monoamine Transporter. LID - 10.3390/ijms222312995 [doi] LID - 12995 AB - 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-alpha-pyrrolidinovalerophenone (R- and S-alpha-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. FAU - Angenoorth, Thomas J F AU - Angenoorth TJF AUID- ORCID: 0000-0002-6119-0472 AD - Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Wahringerstrasse 13A, 1090 Vienna, Austria. FAU - Stankovic, Stevan AU - Stankovic S AD - Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Wahringerstrasse 13A, 1090 Vienna, Austria. FAU - Niello, Marco AU - Niello M AUID- ORCID: 0000-0002-0518-5791 AD - Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Wahringerstrasse 13A, 1090 Vienna, Austria. FAU - Holy, Marion AU - Holy M AD - Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Wahringerstrasse 13A, 1090 Vienna, Austria. FAU - Brandt, Simon D AU - Brandt SD AUID- ORCID: 0000-0001-8632-5372 AD - School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool L3 3AF, UK. FAU - Sitte, Harald H AU - Sitte HH AUID- ORCID: 0000-0002-1339-7444 AD - Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Wahringerstrasse 13A, 1090 Vienna, Austria. FAU - Maier, Julian AU - Maier J AUID- ORCID: 0000-0001-6016-1947 AD - Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Wahringerstrasse 13A, 1090 Vienna, Austria. LA - eng GR - DOC33-B27/FWF Austrian Science Fund/ GR - CS 15-033/Vienna Science and Technology Fund/ GR - W1232/FWF Austrian Science Fund/ GR - W 1232/FWF_/Austrian Science Fund FWF/Austria GR - 2020/Theodor Korner Fonds/ PT - Journal Article DEP - 20211130 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (Dopamine Plasma Membrane Transport Proteins) RN - 0 (Equilibrative Nucleoside Transport Proteins) RN - 0 (GABA Plasma Membrane Transport Proteins) RN - 0 (Octamer Transcription Factors) RN - 0 (Organic Cation Transporter 1) RN - 0 (Organic Cation Transporter 2) RN - 0 (Psychotropic Drugs) RN - 0 (Pyrrolidines) RN - 0 (SLC29A4 protein, human) RN - 0 (SLC6A1 protein, human) RN - 0 (Serotonin Plasma Membrane Transport Proteins) RN - 0 (Vesicular Monoamine Transport Proteins) RN - 0 (alpha-pyrrolidinovalerophenone) RN - 0DHU5B8D6V (Citalopram) RN - 4764-17-4 (3,4-Methylenedioxyamphetamine) RN - ML1I4KK67B (3,4-methylenedioxyethamphetamine) SB - IM MH - 3,4-Methylenedioxyamphetamine/analogs & derivatives/pharmacology MH - Cell Line MH - Central Nervous System/drug effects MH - Citalopram/pharmacology MH - Dopamine Plasma Membrane Transport Proteins/metabolism MH - Equilibrative Nucleoside Transport Proteins/*metabolism MH - GABA Plasma Membrane Transport Proteins/*metabolism MH - HEK293 Cells MH - Humans MH - Octamer Transcription Factors/*metabolism MH - Organic Cation Transporter 1/*metabolism MH - Organic Cation Transporter 2/*metabolism MH - Psychotropic Drugs/*pharmacology MH - Pyrrolidines/pharmacology MH - Serotonin Plasma Membrane Transport Proteins/metabolism MH - Vesicular Monoamine Transport Proteins/metabolism PMC - PMC8657792 OTO - NOTNLM OT - O-desmethyltramadol OT - bupropion OT - cocaine OT - d-amphetamine OT - diazepam OT - escitalopram OT - ketamine OT - modafinil OT - psilocybin OT - tramadol COIS- The authors declare no conflict of interest. EDAT- 2021/12/11 06:00 MHDA- 2021/12/21 06:00 PMCR- 2021/11/30 CRDT- 2021/12/10 01:04 PHST- 2021/10/21 00:00 [received] PHST- 2021/11/26 00:00 [revised] PHST- 2021/11/28 00:00 [accepted] PHST- 2021/12/10 01:04 [entrez] PHST- 2021/12/11 06:00 [pubmed] PHST- 2021/12/21 06:00 [medline] PHST- 2021/11/30 00:00 [pmc-release] AID - ijms222312995 [pii] AID - ijms-22-12995 [pii] AID - 10.3390/ijms222312995 [doi] PST - epublish SO - Int J Mol Sci. 2021 Nov 30;22(23):12995. doi: 10.3390/ijms222312995.