Browsing by Author "Kumar, N"
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- ItemComparative 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, LCGrowing 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.
- ItemEfficient access to chromeno[4,3-b]quinolines related to dependensin(© Georg Thieme Verlag Stuttgart, 2017-08-08) Dobrowolski, JC; Fraser, BH; Bhadbhade, MM; Black, DS; Kumar, NWe report a robust synthesis of novel chromeno[4,3-b]quinoline derivatives structurally similar to the natural product dependensin. The target compounds are accessed through the acid-catalysed condensation of 2-aminoacetophenones or 2-aminochalcones with substituted flavanones, which are in turn obtained from 2-hydroxyacetophenones and benzaldehydes. © 2017 Georg Thieme Verlag Stuttgart
- ItemEvaluation 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, BHAntidepressant-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.
- ItemA general and efficient synthesis of 5,6-dihydrodibenzo[b,h][1,6]naphthyridine derivatives(Elsevier B. V., 2016-12-07) Dobrowolski, JC; Katen, A; Fraser, BH; Bhadbhade, MM; Black, DS; Kumar, NA two-step procedure for the synthesis of dihydrodibenzonaphthyridine derivatives from benzaldehydes and 2-aminoacetophenones, proceeding through a substituted dihydroquinolone intermediate, is described. The synthetic protocol allows for a versatile and robust coupling method between a range of 2-aminoacetophenones or 2-aminobenzophenones and a selection of substituted dihydroquinolones. © 2016 Elsevier B.V.
- ItemA general synthesis of 7-Phenyl-7,13-dihydro-8H-benzo[6,7]azepino[3,2-c]quinolin-8-ones(Thieme, 2019-02-13) Dobrowolski, JC; Nguyen, DHT; Fraser, BH; Bhadbhade, MM; Black, DS; Kumar, NComplex benzazepinoquinolone scaffolds can be accessed from the reaction of 2-aminoacetophenones and oxindole derivatives and feature the seven-membered azepine ring moiety commonly found in a range of drug molecules. The described reaction is generally applicable and allows for rapid access to a diverse range of new structures with further potential to build more elaborate molecules. © 2021 Georg Thieme Verlag KG
- ItemA general synthesis of benzoazepinoindoles – a new class of heterocycles(Thieme, 2019-10-09) Dobrowolski, JC; Nguyen, DHT; Fraser, BH; Bhadbhade, MM; Black, DS; Kumar, NA new class of heterocyclic compounds, namely the benzoazepinoindolones, has been synthesised through a base-catalysed cyclisation reaction of 1,4-bis(2-aminophenyl)-2-phenylbutane-1,4-dione derivatives and features the prominent seven-membered azepine ring moiety. This synthesis has considerable scope for the rapid generation of more complex structures and is inexpensive and generally applicable. © 2019 Georg Thieme Verlag
- ItemHierarchical assembly of tryptophan zipper peptides into stress-relaxing bioactive hydrogels(Springer Nature, 2023-10-23) Nguyen, AK; Molley, TG; Kardia, E; Ganda, S; Chakraborty, S; Wong, SL; Ruan, JF; Yee, BE; Mata, JP; Vijayan, A; Kumar, N; Tilley, RD; Waters, SA; Kilian, KASoft materials in nature are formed through reversible supramolecular assembly of biological polymers into dynamic hierarchical networks. Rational design has led to self-assembling peptides with structural similarities to natural materials. However, recreating the dynamic functional properties inherent to natural systems remains challenging. Here we report the discovery of a short peptide based on the tryptophan zipper (trpzip) motif, that shows multiscale hierarchical ordering that leads to emergent dynamic properties. Trpzip hydrogels are antimicrobial and self-healing, with tunable viscoelasticity and unique yield-stress properties that allow immediate harvest of embedded cells through a flick of the wrist. This characteristic makes Trpzip hydrogels amenable to syringe extrusion, which we demonstrate with examples of cell delivery and bioprinting. Trpzip hydrogels display innate bioactivity, allowing propagation of human intestinal organoids with apical-basal polarization. Considering these extensive attributes, we anticipate the Trpzip motif will prove a versatile building block for supramolecular assembly of soft materials for biotechnology and medicine. © 2023 Springer Nature Limited. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License.
- ItemProbing the structure of nanochannal arrays by electrostatic force microscopy(World Scientific Publishing Co., 2011-04-01) Murugaraj, P; Kumar, N; Jakubov, T; Mainwaring, DE; Siegele, RElectrostatic force microscopy (EFM) represents a versitile tool for the characterisation of electric and dielectric structures at nanoscale which can be employed to provide charge distributions associated with such nanotopologies. EFM-phase profiles show only the variation of electrostatic force which is strongly influenced by the surface conductivity of nanostructured arrays providing improved definition compared to conventional AFM. Here we apply it to carbon nanochannel arrays embedded within polyimide dielectric matrices. © 2012 World Scientific Publishing Co.