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Synthesis and Biological Evaluation of a New Series of Hexahydro-2H-pyrano[3,2-c]quinolines as Novel Selective σ1 Receptor Ligands

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    Synthesis and Biological Evaluation of a New Series of Hexahydro-2H-pyrano[3,2-c]quinolines as Novel Selective σ1 Receptor Ligands
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    † Drug Discovery and Preclinical Development, Esteve, Baldiri Reixach 4-8, 08028 Barcelona, Spain
    ‡ Crysforma, Institute of Chemical Research of Catalonia (ICIQ), Avinguda Països Catalans 16, E-43007 Tarragona, Spain
    *Phone: 0034934466000. E-mail: [email protected] (J.L.D.); [email protected] (C.A.).
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2013, 56, 9, 3656–3665
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    https://doi.org/10.1021/jm400181k
    Published April 8, 2013
    Copyright © 2013 American Chemical Society
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    Abstract

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    The synthesis and pharmacological activity of a new series of hexahydro-2H-pyrano[3,2-c]quinoline derivatives as potent σ1 receptor (σ1R) ligands are reported. This family, which does not contain the highly basic amino group usually present in other σ1R ligands, showed high selectivity over the σ2 receptor (σ2R). The activity was shown to reside in only one of the four possible diastereoisomers, which exhibited a perfect match with known σ1R pharmacophores. A hit to lead program based on a high-throughput screening hit (8a) led to the identification of compound 32c, with substantially improved activity and physicochemical properties. Compound 32c also exhibited a good ADMET (absorption, distribution, metabolism, excretion, toxicity) profile and was identified as a σ1R antagonist on the basis of its analgesic activity in the mouse capsaicin and formalin models of neurogenic pain.

    Copyright © 2013 American Chemical Society

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    Analytical and characterization data for all the compounds. This material is available free of charge via the Internet at http://pubs.acs.org. CCDC 922502 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge Crystallographic Data Centre, 12 Union Rd., Cambridge CB21EZ, U.K. (fax (+44) 1223-336-033, e-mail [email protected]).

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2013, 56, 9, 3656–3665
    Click to copy citationCitation copied!
    https://doi.org/10.1021/jm400181k
    Published April 8, 2013
    Copyright © 2013 American Chemical Society
    Request reuse permissions

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