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Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases

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    Small Molecules Selectively Targeting Sigma-1 Receptor for the Treatment of Neurological Diseases
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    • Na Ye*
      Na Ye
      Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
      *Phone: +86 (512) 65881161; fax, +86 (512) 65880369; email, [email protected]
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      Orcidhttp://orcid.org/0000-0003-3612-1771
    • Wangzhi Qin
      Wangzhi Qin
      Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
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    • Sheng Tian
      Sheng Tian
      Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
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    • Qingfeng Xu
      Qingfeng Xu
      Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
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    • Eric A. Wold
      Eric A. Wold
      Chemical Biology Program, Department of Pharmacology and Toxicology, and Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555, United States
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      Orcidhttp://orcid.org/0000-0001-6434-7562
    • Jia Zhou*
      Jia Zhou
      Chemical Biology Program, Department of Pharmacology and Toxicology, and Center for Addiction Research, University of Texas Medical Branch, Galveston, Texas 77555, United States
      *Phone:+1 (409) 772-9748; fax, +1 (409) 772-9648; email, [email protected]
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      Orcidhttp://orcid.org/0000-0002-2811-1090
    • Xue-Chu Zhen*
      Xue-Chu Zhen
      Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China
      *Phone: + 86 (512) 65880369; fax, +86 (512) 65880369; email, [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2020, 63, 24, 15187–15217
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    https://doi.org/10.1021/acs.jmedchem.0c01192
    Published October 28, 2020
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    Abstract

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    The sigma-1 (σ1) receptor, an enigmatic protein originally classified as an opioid receptor subtype, is now understood to possess unique structural and functional features of its own and play critical roles to widely impact signaling transduction by interacting with receptors, ion channels, lipids, and kinases. The σ1 receptor is implicated in modulating learning, memory, emotion, sensory systems, neuronal development, and cognition and accordingly is now an actively pursued drug target for various neurological and neuropsychiatric disorders. Evaluation of the five selective σ1 receptor drug candidates (pridopidine, ANAVEX2-73, SA4503, S1RA, and T-817MA) that have entered clinical trials has shown that reaching clinical approval remains an evasive and important goal. This review provides up-to-date information on the selective targeting of σ1 receptors, including their history, function, reported crystal structures, and roles in neurological diseases, as well as a useful collation of new chemical entities as σ1 selective orthosteric ligands or allosteric modulators.

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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2020, 63, 24, 15187–15217
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    https://doi.org/10.1021/acs.jmedchem.0c01192
    Published October 28, 2020
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