Skip to main content

Advertisement

SpringerLink
Log in

First in class (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs as selective CB2 modulators targeting neurodegenerative disorders

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

Abstract

Newly designed pyrrolo[2,1-c][1,4]benzodiazepines tricyclic skeleton has shown potential clusters of cannabinoid receptors CB1/CB2 selective ligands. CB2 plays a critical role in microglial-derived neuroinflammation, where it modulates cell proliferation, migration, and differentiation into M1 or M2 phenotypes. Beginning with computer-based docking studies accounting the recently discovered X-ray crystal structure of CB2, we designed a series of PBD analogs as potential ligands of CB2 and tested their binding affinities. Interestingly, computational studies and theoretical binding affinities of several selected (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs, have revealed the presence of potential selectivity in binding attraction toward CB1 and CB2. Reported here is the discovery of the first representatives of this series of selective binding to CB2. Preliminary data showed that this class of molecules display potential binding efficacy toward the cannabinoid receptors tested. Intriguingly, initial cannabinoid binding assay showed a selective binding affinity of 4g and 4h showed Ki of 0.49 and 4.7 μM toward CB2 receptors while no binding was observed to CB1. The designed leads have shown remarkable stability pattern at the physiological pH magnifying their therapeutic values. We hypothesize that the PBD tricyclic structure offers the molecule an appropriate three-dimensional conformation to fit snugly within the active site of CB2 receptors, giving them superiority over the reported CB2 agonists/inverse agonists. Our findings suggested that the attachment of heterocyclic ring through the condensation of diazepine hydrazone and S- or N-heterocyclic aldehydes enhances the selectivity of CB2 over CB1.

First in class (S,E)-11-[2-(Arylmethylene)hydrazono]-PBD analogs as Selective CB2 modulators Targeting Neurodegenerative Disorders

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CB2:

Cannabinoid Receptor Subtype 2

PBD:

Pyrrolo[2,1-c][1,4]benzodiazepines

AD:

Alzheimer’s Disease

PA:

Parkinson’s Disease

THC:

Tetrahydrocannabinol

CBN:

Cannabinol

References

  1. Gao HM, Hong JS. Why neurodegenerative diseases are progressive: uncontrolled inflammation drives disease progression. Trends Immunol. 2008;29:357–65.

    Article  CAS  Google Scholar 

  2. Brettschneider J, Tredici KD, Lee VM, Trojanowski JQ. Spreading of pathology in neurodegenerative diseases: a focus on human studies. Nat Rev Neurosci. 2015;16:109–20.

    Article  CAS  Google Scholar 

  3. Sonkusare SK, Kaul CL, Ramarao P. Dementia of Alzheimer’s disease and other neurodegenerative disorders—memantine, a new hope. Pharm Res. 2005;51:1–7.

    Article  CAS  Google Scholar 

  4. McPartland JM. Phylogenomic and chemotaxonomic analysis of the endocannabinoid system. Brain Res Rev. 2004;45:18–29.

    Article  CAS  Google Scholar 

  5. Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev. 2008;108:1687–707.

    Article  CAS  Google Scholar 

  6. Aso E, Ferrer I. Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Front Pharm. 2014;5:37.

    Article  Google Scholar 

  7. Pacher P, Bátkai S, Kunos G. The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharm Rev. 2006;58:389–462.

    Article  CAS  Google Scholar 

  8. Dhopeshwarkar A, Mackie K. CB2 Cannabinoid receptors as a therapeutic target-what does the future hold? Mol Pharm. 2014;86:430–7.

    Article  Google Scholar 

  9. Contino M, Capparelli E, Colabufo NA, Bush AI. Editorial: the CB2 Cannabinoid System: a new strategy in neurodegenerative disorder and neuroinflammation. Front Neurosci. 2017;11:196.

    Article  Google Scholar 

  10. Lynn AB, Herkenham M. Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor- mediated immune modulation by cannabinoids. J Pharm Exp Ther. 1994;268:1612–23.

    CAS  Google Scholar 

  11. Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, et al. CB2 receptor-mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci. 2006;23:1530–8.

    Article  CAS  Google Scholar 

  12. Mukhopadhyay S, Das S, Williams EA, Moore D, Jones JD, Zahm DS. et al. Lypopolysaccharide and cyclic AMP regulation of CB2 cannabinoid receptor levels in rat brain and mouse RAW 264.7 macrophages. J Neuroimmunol. 2006;181:82–92.

    Article  CAS  Google Scholar 

  13. Nakagawa Y, Chiba K. Role of microglial m1/m2 polarization in relapse and remission of psychiatric disorders and diseases. Pharmaceuticals. 2014;7:1028–48.

    Article  CAS  Google Scholar 

  14. Aso E, Andres-Benito P, Carmona M, Maldonado R, Ferrer I. Cannabinoid receptor 2 participates in amyloid-beta processing in a mouse model of Alzheimer’s disease but plays a minor role in the therapeutic properties of a cannabis-based medicine. J Alzheimers Dis. 2016;51:489–500.

    Article  CAS  Google Scholar 

  15. Aso E, Juves S, Maldonado R, Ferrer I. CB2 cannabinoid receptor agonist ameliorates Alzheimer-like phenotype in AbetaPP/PS1 mice. J Alzheimers Dis. 2013;35:847–58.

    Article  Google Scholar 

  16. Martin-Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, et al. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflamm. 2012;9:8.

    Article  CAS  Google Scholar 

  17. Hebert LE, Weuve J, Scherr PA, Evans DA. Alzheimer disease in the United States (2010–250) estimated using the 2010 census. Neurology. 2013;80:1778–83.

    Article  Google Scholar 

  18. Anavi-Goffer S, Gertsch J. Ariel University Research and Development Co Ltd, 2016. CB2 receptor ligands for the treatment of psychiatric disorders. U.S. Patent 9,486,419.

  19. Cipolla L, Araújo AC, Airoldi C, Bini D. Pyrrolo[2,1-c][1,4]benzodiazepine as a scaffold for the design and synthesis of anti-tumour drugs. Anticancer Agents Med Chem. 2009;9:1–31.

    Article  CAS  Google Scholar 

  20. El-Shaheny R, Radwan MO, Belal F, Yamada K. Pentabromobenzyl-RP versus triazole-HILIC columns for separation of the polar basic analytes famotidine and famotidone: LC method development combined with in silico tools to follow the potential consequences of famotidine gastric instability. J Pharm Biomed Anal. 2020;18:113305.

    Article  Google Scholar 

  21. El-Shaheny R, Radwan M, Yamada K, El-Maghrabey M. Estimation of nizatidine gastric nitrosatability and product toxicity via an integrated approach combining HILIC, in silico toxicology, and molecular docking. J Food Drug Anal. 2019;27:915–25.

    Article  CAS  Google Scholar 

  22. Lange JH, Coolen HK, van Stuivenberg HH, Dijksman JA, Herremans AH, Ronken E, et al. Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB1 cannabinoid receptor antagonists. J Med Chem. 2004;47:627–43.

    Article  CAS  Google Scholar 

  23. Papahatjis DP, Nikas SP, Kourouli T, Chari R, Xu W, Pertwee RG, et al. Pharmacophoric requirements for the cannabinoid side chain. Probing the cannabinoid receptor subsite at C1’. J Med Chem. 2003;46:3221–9.

    Article  CAS  Google Scholar 

  24. Griffin G, Wray EJ, Tao Q, McAllister SD, Rorrer WK, Aung MM, et al. Evaluation of the cannabinoid CB2 receptor-selective antagonist SR144528: further evidence for cannabinoid CB2 receptor absence in the rat central nervous system. Eur J Pharm. 1999;377:117–25.

    Article  CAS  Google Scholar 

  25. Hua T, Vemuri K, Nikas SP, Laprairie RB, Wu Y, Qu L, et al. Crystal structures of agonist-bound human cannabinoid receptor CB1. Nature. 2017;547:468–71.

    Article  CAS  Google Scholar 

  26. Khan N, Halim SA, Khan W, Zafar SK, Ul-Haq Z. In-silico designing and characterization of binding modes of two novel inhibitors for CB1 receptor against obesity by classical 3D-QSAR approach. J Mol Graph Model. 2019;1:199–214.

    Article  Google Scholar 

  27. Kumar KK, Shalev-Benami M, Robertson MJ, Hu H, Banister SD, Hollingsworth SA, et al. Structure of a signaling cannabinoid receptor 1-G protein complex. Cell. 2019;176:448–58.

    Article  Google Scholar 

  28. Shao Z, Yin J, Chapman K, Grzemska M, Clark L, Wang J, et al. High-resolution crystal structure of the human CB1 cannabinoid receptor. Nature. 2016;540:602–6.

    Article  CAS  Google Scholar 

  29. Li X, Hua T, Vemuri K, Ho JH, Wu Y, Wu L, et al. Crystal structure of the human cannabinoid receptor CB2. Cell. 2019;176:459–67.

    Article  CAS  Google Scholar 

  30. Porter RF, Szczesniak AM, Toguri JT, Gebremeskel S, Johnston B, Lehmann C, et al. Selective Cannabinoid 2 Receptor Agonists as Potential Therapeutic Drugs for the Treatment of Endotoxin-Induced Uveitis. Molecules. 2019;24:3338.

    Article  CAS  Google Scholar 

  31. Pertwee RG, Howlett AC, Abood ME, Alexander SP, Di Marzo V, Elphick MR, et al. International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid receptors and their ligands. Beyond CB1 and CB2. Pharm Rev. 2010;62:588–631.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are thankful to the Neuropharmacology CORE (CORE-NPN), School of Pharmacy, University of Mississippi for biological testing. The authors acknowledge the Department of Chemistry and The School of Graduate Studies at ETSU. This work is supported by the National Institute of General Medical Science of the National Institute of Health under Award Number P30GM122733. We are also grateful for the financial support of the ETSU Office of Research and Sponsored Programs Administration (ORSPA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Author notes

  1. These authors contributed equally: Abbas G. Shilabin, Mohamed A. Ibrahim

Authors and Affiliations

  1. Department of Chemistry, East Tennessee State University, Johnson City, TN, 37614, USA

    David Mingle & Abbas G. Shilabin

  2. National Center for Natural Products Research, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Meirambek Ospanov, Samir A. Ross, Larry A. Walker & Mohamed A. Ibrahim

  3. Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Kumamoto University, Kumamoto, 862-0973, Japan

    Mohamed O. Radwan & Masami Otsuka

  4. Department of Drug Discovery, Science Farm Ltd., Kumamoto, 862-0976, Japan

    Mohamed O. Radwan & Masami Otsuka

  5. Chemistry of Natural Compounds Department, Pharmaceutical and Drug Industries Research Division, National Research Centre, Dokki, Cairo, 12622, Egypt

    Mohamed O. Radwan & Mohamed A. Ibrahim

  6. Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, 38677, USA

    Nicole Ashpole & Samir A. Ross

Authors
  1. David Mingle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Meirambek Ospanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mohamed O. Radwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Nicole Ashpole
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Masami Otsuka
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samir A. Ross
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Larry A. Walker
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Abbas G. Shilabin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mohamed A. Ibrahim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Abbas G. Shilabin or Mohamed A. Ibrahim.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mingle, D., Ospanov, M., Radwan, M.O. et al. First in class (S,E)-11-[2-(arylmethylene)hydrazono]-PBD analogs as selective CB2 modulators targeting neurodegenerative disorders. Med Chem Res 30, 98–108 (2021). https://doi.org/10.1007/s00044-020-02640-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00044-020-02640-2

Keywords

Search

Navigation