Browsing by Author "Koek, W"

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    Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter
    (Elsevier B. V., 2019-01) Fraser-Spears, R; Krause-Heuer, AM; Basiouny, M; Mayer, FP; Manishimwe, M; Wyatt, NA; Dobrowolski, JC; Roberts, MP; Greguric, I; Kumar, N; Koek, W; Sitte, HH; Callaghan, PD; Fraser, BH; Daws, LC
    Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [3H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [3H]citalopram, [3H]nisoxetine and [3H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders. © 2021 Elsevier B.V.
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    Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22
    (Elsevier B. V., 2017-09-08) Krause-Heuer, AM; Fraser-Spears, R; Dobrowolski, JC; Ashford, ME; Wyatt, NA; Roberts, MP; Gould, GG; Cheah, WC; Ng, CKL; Bhadbhade, MM; Zhang, B; Greguric, I; Wheate, NJ; Kumar, N; Koek, W; Callaghan, PD; Daws, LC; Fraser, BH
    Antidepressant-like activity Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1–7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1–7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. © 2017 Elsevier B.V.
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    Novel decynium 22 analogs are potent and selective inhibitors of organic cation transporter-3
    (Springer, 2015-12-03) Fraser-Spears, R; Owens, WA; Wyatt, NA; Krause-Heuer, AM; Greguric, I; Callaghan, PD; Fraser, BH; Koek, W; Daws, LC
    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