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Discovery of novel, selective, functionalized 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone sigma-2 ligands

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Abstract

The sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein)). This protein has been linked to diseases and conditions such as Niemann-Pick disease, schizophrenia, neuropathic pain, traumatic brain injury, cancer, drug addiction, and Alzheimer’s disease. The therapeutic utility of σ2 ligands is under investigation in numerous laboratories and on-going clinical trials. Herein, we report the identification of a series of novel 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone and their evaluation using in vitro σ2 and sigma-1 (σ1) assays to determine their σ1/σ2 selectivity profiles, as well as a series of in vitro ADME assays.

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Acknowledgements

Ki determinations for compound binding to Sigma-1, and Sigma-2 were generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is directed by Bryan L. Roth at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA. For experimental details please refer to the PDSP web site https://pdsp.unc.edu/ims/investigator/web/. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. TPSA and cLogP values were generated using the Dotmatics software suite (Dotmatics LLC The Old Monastery, Windhill Bishops, Stortford Herts, CW23 2ND UK).

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Authors and Affiliations

  1. Moulder Center for Drug Discovery Research, Department of Pharmaceutical Sciences, Temple School of Pharmacy, Philadelphia, PA, 19140, USA

    Benjamin E. Blass, John C. Gordon & Daniel J. Canney

  2. Praeventix, Inc., 665 Stockton Drive, Suite 200H, Exton, PA, 19341, USA

    Kevin M. Blattner & Douglas A. Pippin

  3. Institute for Computational Molecular Science, College of Science and Technology, Department of Chemistry, Temple University, Philadelphia, PA, 19140, USA

    Khaled M. Elokely

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  1. Benjamin E. Blass
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Correspondence to Benjamin E. Blass.

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BEB and DJC both have equity interests in Praeventix LLC, which have been reviewed and approved by Temple University in accordance with its conflict of interest policies. Questions regarding this interest may be directed to the Temple University Conflict of Interest Program. No other author has reported conflicts of interest to disclose at the time of publication.

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Blass, B.E., Blattner, K.M., Gordon, J.C. et al. Discovery of novel, selective, functionalized 5-(2-(5-arylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)ethyl)-γ-butyrolactone sigma-2 ligands. Med Chem Res 31, 1209–1223 (2022). https://doi.org/10.1007/s00044-022-02909-8

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