Novel decynium 22 analogs are potent and selective inhibitors of organic cation transporter-3
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Date
2015-12-03
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Publisher
Springer
Abstract
Background: Low-affinity, high-capacity transporters for biogenic amines help regulate neurotransmitter homeostasis. They include the plasma membrane monoamine transporter (PMAT) and three organic cation transporter isoforms (OCT1-3). Our published data, using decynium-22 (D22), a non-selective blocker of PMAT and OCTs, suggests OCT3 and/or PMAT limit the therapeutic efficacy of selective serotonin reuptake inhibitors (SSRI). To aid in discerning the precise transporter(s) involved, we have characterized newly synthesized D22 analogs to identify PMAT and OCT isoform selective compounds.
Methods: Effects of ANSTO analogs on locomotor activity and antidepressant-like behaviors were assessed in adult male, wild type (WT) mice using beam break measurements and the tail suspension test (TST). The activity of 7 analogs (ANSTO 301-307) to inhibit [3H]MPP+ uptake were measured in synaptosomes and HEK cells stably expressing human PMAT, OCT2 or OCT3.
Results: Unlike D22, locomotor activity was not fully suppressed at higher doses up to 1.0 mg/kg, of ANSTO analogs 301, 303-306, and up to 10 mg/kg for ANSTO 307. Similarly to D22, ANSTO compounds (up to 1.0 mg/kg) did not show an antidepressant-like effect in the TST when given alone, however at 3.2 mg/kg, ANSTO 305 and 306 produced antidepressant-like effects. In synaptosomes, all ANSTO compounds, with the exception of analogs 303 and 306, inhibited [3H]MPP+ uptake more potently than D22. In contrast, ANSTO compounds were less potent than D22 and shifted [3H]MPP+ uptake 1- or 2 log-rightward in OCT3-HEK cells. ANSTO analogs displayed similar potencies to corticosterone, which is a blocker of OCT3. ANSTO analogs inhibited [3H]MPP+ uptake through OCT3 more favorably than PMAT (except analog 302) and OCT2 (except analogs 301 & 302).
Conclusions: The significantly enhanced potency for several ANSTO compounds to inhibit [3H]MPP+ uptake in OCT3-HEK cells suggests these compounds may have higher affinity for OCT3 than PMAT or OCT2. Studies measuring behavioral outcomes and competition assays with an SSRI in WT, OCT3 knockout & PMAT knockout mice for physiological comparisons to cell overexpression systems are underway. These studies will reveal more about the pharmacological profile of these novel compounds and their potential therapeutic application to treat disorders, such as depression and drug abuse. © 2022 Springer Nature Limited
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Keywords
Enzyme inhibitors, Cations, Uptake, Antidepressants, Psychotropic drugs, Serotonin, Organic compounds, ANSTO
Citation
Fraser-Spears, R., Owens, W. A., Wyatt, N., Krause-Heuer, A. M., Greguric. I., Callaghan, P. D.., Fraser, B. H., Koek, W., & Daws, L. (2015). Novel decynium 22 analogs are potent and selective inhibitors of organic cation transporter-3. Poaster presented to the 54th Annual Meeting the American College of Neuropsychnpharmacology, December 6-10, 2015, Diplomat Resort and Spa Hollywood, Florida. In Poster Session II. Neuropsychopharmacol 40(1), S272–S442 (2015). doi:10.1038/npp.2015.326