Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

SCH23390 is a widely used D1 dopamine receptor (D1R) antagonist that also elicits some D1R-independent effects. We previously found that the benzazepine, SKF83959, an analog of SCH23390, produces positive allosteric modulation of the Sigma-1 receptor (Sig1R). SCH23390 does not bind to the orthodoxic site of Sig1R but enhances the binding of 3H (+)-pentazocine to Sig1R. In this study, we investigated whether SCH23390 functions as an allosteric modulator of Sig1R. We detected increased Sig1R dissociation from binding immunoglobulin protein (BiP) and translocation of Sig1R to the plasma membrane in response to SCH23390 in transfected HEK293T and SH-SY5Y cells, respectively. Activation of Sig1R by SCH23390 was further confirmed by inhibition of GSK3β activity in a time- and dose-dependent manner; this effect was blocked by pretreatment with the Sig1R antagonist, BD1047, and by knockdown of Sig1R. SCH23390 also inhibited GSK3β in wild-type mice but not in Sig1R knockout mice. Finally, we showed that SCH23390 allosterically modulated the effect of the Sig1R agonist SKF10047 on inhibition of GSK3β. This positive allosteric effect of SCH23390 was further confirmed via promotion of neuronal protection afforded by SKF10047 in primary cortical neurons challenged with MPP+. These results provide the first evidence that SCH23390 elicits functional allosteric modulation of Sig1R. Our findings not only reveal novel pharmacological effects of SCH23390 but also indicate a potential mechanism for SCH23390-mediated D1R-independent effects. Therefore, attention should be paid to these Sig1R-mediated effects when explaining pharmacological responses to SCH23390.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: SCH23390 promotes the dissociation of Sig1R from BiP.
Fig. 2: SCH23390 promotes phosphorylation of GSK3β (Ser9) and Akt (Thr308) in neuronal cells.
Fig. 3: Sig1R mediates inhibition of GSK3β by SCH23390.
Fig. 4: SCH23390 administration inhibits prefrontal cortical GSK3β via Sig1R in vivo.
Fig. 5: SCH23390 modulates the activity of GSK3β via allosteric modulation of Sig1R in neuronal cells.
Fig. 6: SCH23390 synergistically promotes the neuroprotective effect of the Sig1R agonist, SKF10047.
Fig. 7: Pharmacological effect of SCH23390 on Sig1R.

Similar content being viewed by others

References

  1. Bourne JA. SCH 23390: the first selective dopamine D1-like receptor antagonist. CNS Drug Rev. 2001;7:399–414.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Waddington JL, O’Boyle KM. Drugs acting on brain dopamine receptors: a conceptual re-evaluation five years after the first selective D1 antagonist. Pharmacol Ther. 1989;43:1–52.

    Article  CAS  PubMed  Google Scholar 

  3. Arnsten AF, Cai JX, Murphy BL, Goldman-Rakic PS. Dopamine D1 receptor mechanisms in the cognitive performance of young adult and aged monkeys. Psychopharmacology (Berl). 1994;116:143–51.

    Article  CAS  PubMed  Google Scholar 

  4. Kempadoo KA, Mosharov EV, Choi SJ, Sulzer D, Kandel ER. Dopamine release from the locus coeruleus to the dorsal hippocampus promotes spatial learning and memory. Proc Natl Acad Sci USA. 2016;113:14835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Puig MV, Antzoulatos EG, Miller EK. Prefrontal dopamine in associative learning and memory. Neuroscience. 2014;282:217–29.

    Article  CAS  PubMed  Google Scholar 

  6. Tanyeri P, Buyukokuroglu ME, Mutlu O, Ulak G, Akar FY, Celikyurt IK, et al. Effects of ziprasidone, SCH23390 and SB277011 on spatial memory in the Morris water maze test in naive and MK-801 treated mice. Pharmacol Biochem Behav. 2015;138:142–7.

    Article  CAS  PubMed  Google Scholar 

  7. Tao YM, Yu C, Wang WS, Hou YY, Xu XJ, Chi ZQ, et al. Heteromers of mu opioid and dopamine D1 receptors modulate opioid-induced locomotor sensitization in a dopamine-independent manner. Br J Pharmacol. 2017;174:2842–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Nesbit MO, Chai A, Axerio-Cilies P, Phillips AG, Wang YT, Held K. The selective dopamine D1 receptor agonist SKF81297 modulates NMDA receptor currents independently of D1 receptors. Neuropharmacology. 2022;207:108967.

    Article  CAS  PubMed  Google Scholar 

  9. Yu Y, Wang JR, Sun PH, Guo Y, Zhang ZJ, Jin GZ, et al. Neuroprotective effects of atypical D1 receptor agonist SKF83959 are mediated via D1 receptor-dependent inhibition of glycogen synthase kinase-3 beta and a receptor-independent anti-oxidative action. J Neurochem. 2008;104:946–56.

    Article  CAS  PubMed  Google Scholar 

  10. Guo L, Zhao J, Jin G, Zhao B, Wang G, Zhang A, et al. SKF83959 is a potent allosteric modulator of sigma-1 receptor. Mol Pharmacol. 2013;83:577–86.

    Article  CAS  PubMed  Google Scholar 

  11. Fukunaga K, Moriguchi S. Stimulation of the sigma-1 receptor and the effects on neurogenesis and depressive behaviors in mice. Adv Exp Med Biol. 2017;964:201–11.

    Article  CAS  PubMed  Google Scholar 

  12. Hashimoto K. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication. J Pharmacol Sci. 2015;127:6–9.

    Article  CAS  PubMed  Google Scholar 

  13. Wang Y, Guo L, Jiang HF, Zheng LT, Zhang A, Zhen XC. Allosteric modulation of sigma-1 receptors elicits rapid antidepressant activity. CNS Neurosci Ther. 2016;22:368–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18:e3000410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang G, Chen S, Jia J, Liu C, Wang W, Zhang H, et al. Development and evaluation of novel metformin derivative metformin threonate for brain ischemia treatment. Front Pharmacol. 2022;13:879690.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zhang G, Li Q, Tao W, Qin P, Chen J, Yang H, et al. Sigma-1 receptor-regulated efferocytosis by infiltrating circulating macrophages/microglial cells protects against neuronal impairments and promotes functional recovery in cerebral ischemic stroke. Theranostics. 2023;13:543–59.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang M, Wan C, He T, Han C, Zhu K, Waddington JL, et al. Sigma-1 receptor regulates mitophagy in dopaminergic neurons and contributes to dopaminergic protection. Neuropharmacology. 2021;196:108360.

    Article  CAS  PubMed  Google Scholar 

  18. Lasbleiz C, Peyrel A, Tarot P, Sarniguet J, Crouzier L, Cubedo N, et al. Sigma-1 receptor agonist PRE-084 confers protection against TAR DNA-binding protein-43 toxicity through NRF2 signalling. Redox Biol. 2022;58:102542.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yano H, Bonifazi A, Xu M, Guthrie DA, Schneck SN, Abramyan AM, et al. Pharmacological profiling of sigma 1 receptor ligands by novel receptor homomer assays. Neuropharmacology. 2018;133:264–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Huang W, Zuo W, Chen L, Wang L, Tewfik G, Fu R, et al. Acetaldehyde excitation of lateral habenular neurons via multiple cellular mechanisms. J Neurosci. 2021;41:7532–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Calvo B, Fernandez M, Rincon M, Tranque P. GSK3beta inhibition by phosphorylation at Ser(389) controls neuroinflammation. Int J Mol Sci. 2022;24:337.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Yan N, Xie F, Tang LQ, Wang DF, Li X, Liu C, et al. Synthesis and biological evaluation of thieno[3,2-c]pyrazol-3-amine derivatives as potent glycogen synthase kinase 3beta inhibitors for Alzheimer’s disease. Bioorg Chem. 2023;138:106663.

    Article  CAS  PubMed  Google Scholar 

  23. Alexander SP, Benson HE, Faccenda E, Pawson AJ, Sharman JL, McGrath JC, et al. The concise guide to PHARMACOLOGY 2013/14: overview. Br J Pharmacol. 2013;170:1449–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Alon A, Schmidt HR, Wood MD, Sahn JJ, Martin SF, Kruse AC. Identification of the gene that codes for the sigma(2) receptor. Proc Natl Acad Sci USA. 2017;114:7160–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Haller JL, Panyutin I, Chaudhry A, Zeng C, Mach RH, Frank JA. Sigma-2 receptor as potential indicator of stem cell differentiation. Mol Imaging Biol. 2012;14:325–35.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Hellewell SB, Bruce A, Feinstein G, Orringer J, Williams W, Bowen WD. Rat liver and kidney contain high densities of sigma 1 and sigma 2 receptors: characterization by ligand binding and photoaffinity labeling. Eur J Pharmacol. 1994;268:9–18.

    Article  CAS  PubMed  Google Scholar 

  27. Quirion R, Bowen WD, Itzhak Y, Junien JL, Musacchio JM, Rothman RB, et al. A proposal for the classification of sigma binding sites. Trends Pharmacol Sci. 1992;13:85–6.

    Article  CAS  PubMed  Google Scholar 

  28. Chen AF, Ma WH, Xie XY, Huang YS. Sigma-2 receptor as a potential drug target. Curr Med Chem. 2021;28:4172–89.

    Article  CAS  PubMed  Google Scholar 

  29. Riad A, Lengyel-Zhand Z, Zeng C, Weng CC, Lee VM, Trojanowski JQ, et al. The sigma-2 receptor/TMEM97, PGRMC1, and LDL receptor complex are responsible for the cellular uptake of Abeta42 and its protein aggregates. Mol Neurobiol. 2020;57:3803–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vavers E, Zvejniece L, Dambrova M. Sigma-1 receptor and seizures. Pharmacol Res. 2023;191:106771.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ye N, Qin W, Tian S, Xu Q, Wold EA, Zhou J, et al. Small molecules selectively targeting sigma-1 receptor for the treatment of neurological diseases. J Med Chem. 2020;63:15187–217.

    Article  CAS  PubMed  Google Scholar 

  32. Hayashi T, Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell. 2007;131:596–610.

    Article  CAS  PubMed  Google Scholar 

  33. Maurice T. Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders. Expert Opin Drug Discov. 2021;16:373–89.

    Article  CAS  PubMed  Google Scholar 

  34. Crouzier L, Couly S, Roques C, Peter C, Belkhiter R, Arguel Jacquemin M, et al. Sigma-1 (sigma(1)) receptor activity is necessary for physiological brain plasticity in mice. Eur Neuropsychopharmacol. 2020;39:29–45.

    Article  CAS  PubMed  Google Scholar 

  35. Jia J, Cheng J, Wang C, Zhen X. Sigma-1 receptor-modulated neuroinflammation in neurological diseases. Front Cell Neurosci. 2018;12:314.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ryskamp DA, Korban S, Zhemkov V, Kraskovskaya N, Bezprozvanny I. Neuronal sigma-1 receptors: signaling functions and protective roles in neurodegenerative diseases. Front Neurosci. 2019;13:862.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Su TP, Su TC, Nakamura Y, Tsai SY. The sigma-1 receptor as a pluripotent modulator in living systems. Trends Pharmacol Sci. 2016;37:262–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Vavers E, Zvejniece L, Maurice T, Dambrova M. Allosteric modulators of sigma-1 receptor: a review. Front Pharmacol. 2019;10:223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Guo L, Chen Y, Zhao R, Wang G, Friedman E, Zhang A, et al. Allosteric modulation of sigma-1 receptors elicits anti-seizure activities. Br J Pharmacol. 2015;172:4052–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zvejniece L, Vavers E, Svalbe B, Vilskersts R, Domracheva I, Vorona M, et al. The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors. Br J Pharmacol. 2014;171:761–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wu Z, Li L, Zheng LT, Xu Z, Guo L, Zhen X. Allosteric modulation of sigma-1 receptors by SKF83959 inhibits microglia-mediated inflammation. J Neurochem. 2015;134:904–14.

    Article  CAS  PubMed  Google Scholar 

  42. Scerbina T, Chatterjee D, Gerlai R. Dopamine receptor antagonism disrupts social preference in zebrafish: a strain comparison study. Amino Acids. 2012;43:2059–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the National Key Research and Development Program of China (2021YFE0206000), STI2030-Major Projects (2021ZD0204004), the National Natural Science Foundation of China (81973334, 81773702, 82003769). Support from Suzhou Gusu Health Talent Scientific Research Project (GSWS2021053) is also appreciated.

Author information

Author notes

  1. These authors contributed equally: Gu-fang Zhang, Kai-lian Zhu

Authors and Affiliations

  1. Jiangsu Key Laboratory of Neuropsychiatric Diseases and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, 215123, China

    Gu-fang Zhang, Kai-lian Zhu, Qi Li, John L. Waddington & Xue-chu Zhen

  2. Suzhou Medical College, Soochow University, Suzhou, 215123, China

    Yue Zhang

  3. School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and Health Sciences, Dublin, Ireland

    John L. Waddington

  4. Department of Psychiatry, The Affiliated Guangji Hospital of Soochow University, Suzhou, 215003, China

    Xiang-dong Du

Authors
  1. Gu-fang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kai-lian Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yue Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. John L. Waddington
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiang-dong Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xue-chu Zhen
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GFZ, KLZ, QL and YZ performed experiments and data analysis; GFZ and KLZ analyzed the data and wrote the original draft; JLW and XDD reviewed the manuscript and developed the results and conclusions; XCZ designed the study and reviewed the manuscript.

Corresponding authors

Correspondence to Xiang-dong Du or Xue-chu Zhen.

Ethics declarations

Competing interests

The authors declare no competing interests.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, Gf., Zhu, Kl., Li, Q. et al. The classical D1 dopamine receptor antagonist SCH23390 is a functional sigma-1 receptor allosteric modulator. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01256-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41401-024-01256-1

Keywords

Search

Advanced search

Quick links