Skip to main content

Advertisement

SpringerLink
Log in

Design, synthesis, and evaluation of novel, selective γ-butyrolactones sigma-2 ligands

  • Original Research
  • Published:
Medicinal Chemistry Research Aims and scope Submit manuscript

Abstract

Nearly 40 years after the first disclosure of sigma receptors, the sigma-2 (σ2) receptor was recently identified as the Transmembrane Protein 97 (TMEM97, also known as MAC30 (Meningioma-associated protein). This macromolecule has been associated with a number of disease states such as schizophrenia, Alzheimer’s disease, neuropathic pain, traumatic brain injury, and cancer. We have recently identified a series of novel, functionalized γ-butyrolactones that are potent σ2 receptor ligands that are drug-like and identified a potential candidate (9z) for future in vivo study.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Scheme 1

Similar content being viewed by others

References

  1. Martin WR, Eades CE, Thompson JA, Huppler RE. The effects of morphine and nalorphine-like drugs in the non-dependent and morphine-dependent chronic spinal dog. J Pharm Exp Ther. 1976;197:517–32. PMID: 945347.

    CAS  Google Scholar 

  2. Su TP. Evidence for sigma opioid receptor: binding of [3H]SKF-10047 to etorphine inaccessible sites in guinea-pig brain. J Pharmacol Exp Ther 1982;223:284–90. https://doi.org/10.1007/s00044-020-02574-9.

    Article  CAS  PubMed  Google Scholar 

  3. Khazan N, Young GA, El-Fakany EE, Hong O, Caliigaro D. Sigma receptors mediated the psychotomimetic effects of N-allylnormetazocine (SKF-10,047), but not its opioid agonistic-antagonistic properties. Neuropharmacology. 1984b;23:983–7. https://doi.org/10.1016/0028-3908(84)90015-7.

    Article  CAS  PubMed  Google Scholar 

  4. Bowen WD, de Costa BR, Hellewell SB, Walker JM, Rice KC. [3H]-(+)-Pentazocine: a potent and highly selective benzomorphan-based probe for sigma-1 receptors. Mol Neuropharmacol. 1993;3:117–26.

    CAS  Google Scholar 

  5. Hanner M, Moebius FF, Flandorfer A, Knaus HG, Striessnig J, Kepner E, et al. Purification, molecular cloning, and expression of the mammalian sigma-1 binding site. Proc Natl Acad Sci USA. 1996;93:8072–77. https://doi.org/10.1073/pnas.93.15.8072. 23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Schmidt HR, Zheng S, Guripinar E, Koehl A, Manglik A, Kruse AC. Crystal structure of the human σ1 receptor. Nature 2016;532:527–30. https://doi.org/10.1038/nature17391. 28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Krusea AC. Identification of the gene that codes for the σ2. receptor, Proc Natl Acad Sci U S A 2017;114:7160–5. https://doi.org/10.1073/pnas.1705154114.

    Article  CAS  PubMed  Google Scholar 

  8. Bartz F, Kern L, Erz D, Zhu M, Gilbert D, Meinhof T, et al. Identification of cholesterol-regulating genes by targeted RNAi screening. Cell Metab. 2009;10:63–75. https://doi.org/10.1016/j.cmet.2009.05.009.

    Article  CAS  PubMed  Google Scholar 

  9. Ebrahimi-Fakhar D, Wahlster L, Bartz F, Werenbeck-Ueding J, Praggastis M, Zhang J, et al. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Hum Mol Genet. 2016;25:3588–99. https://doi.org/10.1093/hmg/ddw204. 15.

    Article  CAS  Google Scholar 

  10. Guo L, Zhen X. Sigma-2 receptor ligands: neurobiological effects. Curr Med Chem 2015;22:989–1003. https://doi.org/10.2174/0929867322666150114163607.

    Article  CAS  PubMed  Google Scholar 

  11. Yi B, Sahn JJ, Ardestani PM, Evans AK, Scott LL, Chan JZ, et al. Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer’s disease. J Neurochem. 2017a;140:561–75. https://doi.org/10.1111/jnc.13917.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Izzo NJ, Staniszewski A, To L, Fa M, Teich AF, Saeed F, et al. Alzheimer’s therapeutics targeting amyloid beta 1−42 oligomers I: Abeta 42 oligomer binding to specific neuronal receptors is displaced by drug candidates that improve cognitive deficits. PLoS One. 2014b;9:e111898 https://doi.org/10.1371/journal.pone.0111898.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Izzo NJ, Xu J, Zeng C, Kirk MJ, Mozzoni K, Silky C, et al. Alzheimer’s therapeutics targeting amyloid beta 1−42 oligomers II: Sigma-2/PGRMC1 receptors mediate Abeta 42 oligomer binding and synaptotoxicity. PLoS One. 2014c;9:e111899 https://doi.org/10.1371/journal.pone.0111899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sahn JJ, Mejia GL, Ray PR, Martin SF, Price TJ. Sigma 2 receptor/Tmem97 agonists produce long lasting antineuropathic pain effects in mice. ACS Chem Neurosci. 2017;8:1801–11. https://doi.org/10.1021/acschemneuro.7b00200.

    Article  CAS  PubMed  Google Scholar 

  15. Vazquez-Rosa E, Watson MR, Sahn JJ, Hodges TR, Schroeder RE, Cintron-Perez CJ, et al. Neuroprotective Efficacy of a Sigma 2 Receptor/TMEM97 Modulator (DKR-1677) after Traumatic Brain Injury. ACS Chem Neurosci. 2019;10:1595–602. https://doi.org/10.1021/acschemneuro.8b00543.

    Article  CAS  PubMed  Google Scholar 

  16. Vilner BJ, John CS, Bowen WD. Sigma-1 and Sigma-2 receptors are expressed in a wide variety of human and rodent tumor cell lines. Cancer Res. 1995a;55:408–13. Jan 15PMID: 7812973.

    CAS  PubMed  Google Scholar 

  17. Asong G, Zhu XY, Bricker B, Andey T, Amissah F, Lamango N, et al. New analogs of SYA013 as sigma-2 ligands with anticancer activity. Bioorg Med Chem. 2019b;27:2629–36. https://doi.org/10.1016/j.bmc.2019.04.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gao R, Bhandare RR, Canney DJ. Homologation as a lead modification approach en route to a series of lactone-based muscarinic ligands. Med Chem Res 2014;23:1023–30. https://doi.org/10.1007/s00044-013-0692-3.

    Article  CAS  Google Scholar 

  19. Gao R, Canney DJ. A modified Prins reaction for the facile synthesis of structurally diverse substituted 5-(2-hydroxyethyl)-3. 3-dihydrofurane-2(3H)-ones Tet Let. 2009;50:5914–16. https://doi.org/10.1016/j.tetlet.2009.08.016.

    Article  CAS  Google Scholar 

  20. Lipinski CA, Lombardo F, Dominy BW, Feeney PJ. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Deliv Rev. 2001;46:3–26. https://doi.org/10.1016/s0169-409x(00)00129-0.

    Article  CAS  PubMed  Google Scholar 

  21. Abate C, Niso M, Berardi F. Sigma-2 receptor: past, present and perspectives on multiple therapeutic exploitations. Future Med Chem. 2018a;10:1997–2018. https://doi.org/10.4155/fmc-2018-0072.

    Article  CAS  PubMed  Google Scholar 

  22. Blass BE, Rogers JP. The sigma-2 (σ-2) receptor: a review of recent patent applications: 2013-8. Expert Opin Ther Pat 2018b;28:655–63. https://doi.org/10.1080/13543776.2018.1519024

    Article  CAS  PubMed  Google Scholar 

  23. Zeng C, Mach RH. The evolution of the sigma-2 (σ2) receptor from obscure binding site to bona fide therapeutic target. Adv Exp Med Biol 2017;964:49–61. https://doi.org/10.1007/978-3-319-50174-1_5.

    Article  CAS  PubMed  Google Scholar 

  24. Gao R Design, synthesis and evaluation of novel muscarinic ligands [Dissertation] Temple University School of Pharmacy, 2013.

  25. Cheng Y, Prusoff WH. Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharm. 1973;22:3099–108. https://doi.org/10.1016/0006-2952(73)90196-2.

    Article  CAS  PubMed  Google Scholar 

  26. McMasters DR, Torres RA, Crathern SJ, Dooney D, Nachbar RB, Sheridan RP, et al. Inhibition of recombinant cytochrome P450 isoforms 2D6 and 2C9 by diverse drug-like molecules. J Med Chem. 2007;50:3205–13. https://doi.org/10.1021/jm0700060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Yang J, Jamei M, Yeo KR, Rostami-Hodjegan A, Tucker GT. Misuse of the well-stirred model of hepatic drug clearance. Drug Metab Dispos 2007;35:501–2. https://doi.org/10.1124/dmd.106.013359.06/23/2021.

    Article  CAS  PubMed  Google Scholar 

Download references

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).

Author information

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, 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

Authors
  1. Benjamin E. Blass
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rong Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kevin M. Blattner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. John C. Gordon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Douglas A. Pippin
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Daniel J. Canney
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Benjamin E. Blass.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.: 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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Blass, B.E., Gao, R., Blattner, K.M. et al. Design, synthesis, and evaluation of novel, selective γ-butyrolactones sigma-2 ligands. Med Chem Res 30, 1713–1727 (2021). https://doi.org/10.1007/s00044-021-02771-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-021-02771-0

Keywords

Search

Navigation