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

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dc.contributor.authorAshford, MEen_AU
dc.contributor.authorNguyen, VHen_AU
dc.contributor.authorGreguric, Ien_AU
dc.contributor.authorPham, TQen_AU
dc.contributor.authorKeller, PAen_AU
dc.contributor.authorKatsifis, Aen_AU
dc.date.accessioned2020-03-11T23:50:37Zen_AU
dc.date.available2020-03-11T23:50:37Zen_AU
dc.date.issued2013-11-28en_AU
dc.date.statistics2020-03-11en_AU
dc.description.abstractAbstract5-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 Chemistryen_AU
dc.identifier.citationAshford, M. E., Nguyen, V. H., Greguric, I., Pham, T. Q., Keller, P. A., & Katsifis, A. (2014). Synthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ 2) selective ligands. Organic & Biomolecular Chemistry, 12(5), 783-794. doi:10.1039/C3OB42254Ben_AU
dc.identifier.govdoc8666en_AU
dc.identifier.issn1477-0520en_AU
dc.identifier.issue5en_AU
dc.identifier.journaltitleOrganic & Biomolecular Chemistryen_AU
dc.identifier.pagination783-794en_AU
dc.identifier.urihttp://doi.org/10.1039/C3OB42254Ben_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/9139en_AU
dc.identifier.volume12en_AU
dc.language.isoenen_AU
dc.publisherThe Royal Society of Chemistryen_AU
dc.subjectLigandsen_AU
dc.subjectReceptorsen_AU
dc.subjectMoleculesen_AU
dc.subjectCarboxylic acidsen_AU
dc.subjectPharmacologyen_AU
dc.subjectNervous system diseasesen_AU
dc.titleSynthesis and in vitro evaluation of tetrahydroisoquinolines with pendent aromatics as sigma-2 (σ2) selective ligandsen_AU
dc.typeJournal Articleen_AU
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