Browsing by Author "Keller, PA"

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    Synthesis and in vitro binding of N,N-Dialkyl-2-phenylindol-3-yl-glyoxylamides for the peripheral benzodiazepine binding sites
    (Pergamon-Elsevier Science Ltd, 2006-06-01) Homes, TP; Mattner, F; Keller, PA; Katsifis, A
    A series of NN-dialkyl-2-phenylindol-3-glyoxylamides bearing the halogens iodine and bromine were synthesised and their binding affinity for the peripheral benzodiazepine binding sites (PBBS) in rat kidney mitochondrial membranes was evaluated Using [H-3]PK11195. Central benzodiazepine receptor (CBR) affinities were also evaluated in rat cortices using [H-3]flumazenil to determine their selectivity for PBBS over CBR. The tested compounds had PBBS binding affinities (IC50) ranging from 7.86 to 618 nM, with all compounds showing high selectivity over the CBR (CBR IC50 > 5000 nM). Among the 12 compounds tested, those with a diethylamide group were the most potent. The highest affinity iodinated PBBS ligand, N,N-diethyl-[5-chloro-2-(4-iodophenyl)indol-3-yl]glyoxylamide (4c), was radiolabelled with iodine-123. This high affinity and selective radioligand may be useful for imaging neurodegencration, inflammation and tumours using single photon emission computed tomography. © 2006, Elsevier Ltd.
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    Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands
    (The Royal Society of Chemistry, 2013-11-28) Ashford, ME; Nguyen, VH; Greguric, I; Pham, TQ; Keller, PA; Katsifis, A
    Abstract5-Bromo-N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-butyl)]-2,3-dimethoxybenzamide 1 is a potent and selective σ2 receptor ligand suitable for further development. A series of new analogues, incorporating a variety of isoquinoline and carboxylic acid moieties, linked together with either a linear or cyclic amine spacer have been synthesised and assessed for their σ1/σ2 binding affinity and selectivity. Compounds with a rigid piperidine spacer gave Ki values for the σ2 receptor between 8.7–845 nM. Changing the configuration of the methoxy groups on the isoquinoline moiety resulted in molecules with σ2Ki values of 4.4–133 nM whereas varying the length and flexibility of the carbon spaces gave σ2Ki values 0.88–15.0 nM, some of the most active, selective σ2 ligands to date. Thus, the flexibility and length of the carbon linker and the carboxylic acid moiety are confirmed to be key to the exceptional binding affinity and selectivity for this active series. Additionally, the incorporation of a halogen on selected carboxylic acid moieties provided a convenient strategy for the introduction of a radiohalogen for applications in pharmacological and imaging studies. © 2014 The Royal Society of Chemistry