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Issue 5, 2014
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Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands

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Abstract

5-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 σ12 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.

Graphical abstract: Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands

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Publication details

The article was received on 13 Nov 2013, accepted on 27 Nov 2013 and first published on 28 Nov 2013


Article type: Paper
DOI: 10.1039/C3OB42254B
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Org. Biomol. Chem., 2014,12, 783-794

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    Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligands

    M. E. Ashford, V. H. Nguyen, I. Greguric, T. Q. Pham, P. A. Keller and A. Katsifis, Org. Biomol. Chem., 2014, 12, 783
    DOI: 10.1039/C3OB42254B

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