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Increased rigidity and bioisosteric replacement in the design, synthesis and preliminary evaluation of novel, functionalized 3,3-dialkyl-γ-butyrolactones as sigma-2 ligands

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Abstract

The sigma-2 (σ2) receptor has been linked to several diseases and conditions including cancer, neuropathic drug addiction, Alzheimer’s disease, Parkinson’s disease, traumatic brain injury, Niemann-Pick disease, schizophrenia, depression, and anxiety. Targeting σ2 as a means of treating these diseases and conditions has been the subject of intense research, and several clinical trials have been launched to determine the real-world therapeutic utility of this target. Herein, we report the identification of a novel, semirigid series of functionalized 3,3-dialkyl-γ-butyrolactone σ2 ligands, containing piperazine bioisosteres. The compounds were evaluated using a variety of in vitro assays to determine affinity for sigma receptors, σ1/ σ2 selectivity profiles, aqueous solubility, and mouse liver microsome stability.

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Acknowledgements

Ki determinations for compound binding to σ1, and σ2 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, Suite 516, Temple School of Pharmacy, 3307 North Broad Street, Philadelphia, PA, 19140, USA

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

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

    Kevin M. Blattner & Douglas A. Pippin

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  1. Benjamin E. Blass
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Correspondence to Daniel J. Canney.

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Drs. Blass and Canney 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., Gao, R., Blattner, K.M. et al. Increased rigidity and bioisosteric replacement in the design, synthesis and preliminary evaluation of novel, functionalized 3,3-dialkyl-γ-butyrolactones as sigma-2 ligands. Med Chem Res 33, 287–297 (2024). https://doi.org/10.1007/s00044-023-03182-z

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