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Journal of Neuroimmune Pharmacology

, Volume 8, Issue 5, pp 1077–1086 | Cite as

Immune-Modulation and Properties of Absorption and Blood Brain Barrier Permeability of 1,8-Naphthyridine Derivatives

  • Anna Maria Malfitano
  • Chiara Laezza
  • Giuseppe Saccomanni
  • Tiziano Tuccinardi
  • Clementina Manera
  • Adriano Martinelli
  • Elena Ciaglia
  • Simona Pisanti
  • Mario Vitale
  • Patrizia Gazzerro
  • Maurizio Bifulco
PERSPECTIVE

Abstract

Considering the high selectivity at the cannabinoid CB2 receptor of recently designed 1,8-naphthyridine derivatives and the protective role of this receptor in neurological disorders, in this study we investigated the immune-modulatory and anti-inflammatory effects of these compounds as well as their potential properties of intestinal absorption and blood–brain barrier (BBB) permeability. We used peripheral blood mononuclear cells (PBMC) known to express the CB2 receptor. We observed that test compounds, CB13, CB82 and CB91 reduced PBMC proliferation. The anti-proliferative effect of CB13 and CB91 was partially mediated by the CB2 receptor. These compounds blocked the cells cycle and CB91 reduced T cell activation. CB82 and CB91 down-regulated the expression of phosphorylated proteins like NF-κB, ERK, Akt and the enzyme Cox-2, CB91 blocked the expression of the CB2 receptor and its inhibitory effect was CB2 receptor mediated. We also investigated CB91 properties of intestinal absorption and BBB permeability in order to suggest its potential efficacy on the infiltrating auto-reactive lymphocytes at the level of the central nervous system. For this purpose, CB91 was tested in drug-permeability assays on Caco-2 cells to evaluate its oral bioavailability and on MDCKII-hMDR1 cells to estimate its BBB permeability. The results indicated that this compound possesses medium level of intestinal absorption and BBB permeability. Our data suggest that CB91, modulating the immune response by CB2 receptor mediated mechanism and showing medium level of intestinal absorption and BBB permeability, might be developed as a potential orally delivered drug and might find potential application in pathologies like multiple sclerosis.

Keywords

CB2 receptor Immune-modulation Intestinal absorption Blood–brain barrier permeability 

Notes

Acknowledgments

This study was supported by FISM -Fondazione Italiana Sclerosi Multipla – Cod. 2009/R/3/C1

(Grant to M.B.), and Associazione Ricerca Medica Salernitana “ERMES”. A.M.M. was supported by a fellowship from FISM -Fondazione Italiana Sclerosi Multipla.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Benavides A, Napolitano A, Bassarello C et al (2009) Oxylipins from Dracontium loretense. J Nat Prod 72(5):813–817PubMedCrossRefGoogle Scholar
  2. Bifulco M, Laezza C, Malfitano AM (2007) From anecdotal evidence of cannabinoids in multiple sclerosis to emerging new therapeutical approaches. Mult Scler 13(1):133–134PubMedCrossRefGoogle Scholar
  3. Cabral, Griffin-Thomas (2009) Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med 20(11):e3CrossRefGoogle Scholar
  4. Cianchi F, Papucci L, Schiavone N et al (2008) Cannabinoid receptor activation induces apoptosis through tumor necrosis factor alpha-mediated ceramide de novo synthesis in colon cancer cells. Clin Cancer Res 14(23):7691–7700PubMedCrossRefGoogle Scholar
  5. Ferrarini PL, Calderone V, Cavallini T et al (2004) Synthesis and biological evaluation of 1,8-naphthyridin-4(1H)-on-3-carboxamide derivatives as new ligands of cannabinoid receptors. Bioorg Med Chem 12:1921–1933PubMedCrossRefGoogle Scholar
  6. Gong JP, Onaivi ES, Ishiguro H et al (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071(1):10–23PubMedCrossRefGoogle Scholar
  7. Hillard CJ, Weinlander KM, Stuhr KL (2012) Contributions of endocannabinoid signaling to psychiatric disorders in humans: genetic and biochemical evidence. Neuroscience 204:207–229PubMedCrossRefPubMedCentralGoogle Scholar
  8. Howlett AC, Barth F, Bonner TI et al (2002) International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmac Rev 54:161–202CrossRefGoogle Scholar
  9. Hsu MH, Liu CY, Lin CM et al (2012) 2-(3-Methoxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (HKL-1) induces G2/M arrest and mitotic catastrophe in human leukemia HL-60 cells. Toxicol Appl Pharmacol 259(2):219–226PubMedCrossRefGoogle Scholar
  10. Jackson SJ, Pryce G, Diemel LT et al (2005) Cannabinoid-receptor 1 null mice are susceptible to neurofilament damage and caspase 3 activation. Neuroscience 134(1):261–268PubMedCrossRefGoogle Scholar
  11. Klein TW, Newton C, Larsen K et al (2003) The cannabinoid system and immune modulation. J Leukoc Biol 74(4):486–496PubMedCrossRefGoogle Scholar
  12. Loría F, Petrosino S, Hernangómez M et al (2010) An endocannabinoid tone limits excitotoxicity in vitro and in a model of multiple sclerosis. Neurobiol Dis 37(1):166–176PubMedCrossRefGoogle Scholar
  13. Malfitano AM, Matarese G, Pisanti S et al (2006) Arvanil inhibits T lymphocyte activation and ameliorates autoimmune encephalomyelitis. J Neuroimmunol 171(1–2):110–119PubMedCrossRefGoogle Scholar
  14. Malfitano AM, Proto MC, Bifulco M (2008) Cannabinoids in the management of spasticity associated with multiple sclerosis. Neuropsychiatr Dis Treat 4(5):847–853PubMedPubMedCentralGoogle Scholar
  15. Malfitano AM, Ciaglia E, Gangemi G et al (2011a) Update on the endocannabinoid system as an anticancer target. Expert Opin Ther Targets 15(3):297–308PubMedCrossRefGoogle Scholar
  16. Malfitano AM, Sosa S, Laezza C et al (2011b) Rimonabant reduces keratinocyte viability by induction of apoptosis and exerts topical anti-inflammatory activity in mice. Br J Pharmacol 162(1):84–93PubMedCrossRefPubMedCentralGoogle Scholar
  17. Malfitano AM, Laezza C, D’Alessandro A et al (2013) Effects on immune cells of a new 1,8-Naphthyridin-2-One derivative and its analogues as selective CB2 agonists: implications in multiple sclerosis. PLoS One 8(5):e62511PubMedCrossRefPubMedCentralGoogle Scholar
  18. Manera C, Benetti V, Castelli MP et al (2006) Design, synthesis, and biological evaluation of new 1,8-naphthyridin-4(1H)-on-3-carboxamide and quinolin-4(1H)-on-3-carboxamide derivatives as CB2 selective agonists. J Med Chem 49(20):5947–5957PubMedCrossRefGoogle Scholar
  19. Manera C, Cascio MG, Benetti V et al (2007) New 1,8-naphthyridine and quinoline derivatives as CB2 selective agonists. Bioorg Med Chem Lett 17(23):6505–6510PubMedCrossRefGoogle Scholar
  20. Manera C, Saccomanni G, Adinolfi B et al (2009) Rational design, synthesis, and pharmacological properties of new 1,8-naphthyridin-2(1H)-on-3-carboxamide derivatives as highly selective cannabinoid-2 receptor agonists. J Med Chem 52(12):3644–3651PubMedCrossRefGoogle Scholar
  21. Manera C, Saccomanni G, Malfitano AM et al (2012) Rational design, synthesis and anti-proliferative properties of new CB2 selective cannabinoid receptor ligands: an investigation of the 1,8-naphthyridin-2(1H)-one scaffold. Eur J Med Chem 52:284–294PubMedCrossRefGoogle Scholar
  22. Maresz K, Carrier EJ, Ponomarev ED et al (2005) Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem 95(2):437–445PubMedCrossRefGoogle Scholar
  23. Matsuda LA, Lolait SJ, Brownstein MJ et al (1990) Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346:561–564PubMedCrossRefGoogle Scholar
  24. Pertwee RG (2009) Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 156(3):397–411PubMedCrossRefPubMedCentralGoogle Scholar
  25. Pryce G, Ahmed Z, Hankey DJ et al (2003) Cannabinoids inhibit neurodegeneration in models of multiple sclerosis. Brain 126(Pt 10):2191–2202PubMedCrossRefGoogle Scholar
  26. Rossi F, Siniscalco D, Luongo L et al (2009) The endovanilloid/endocannabinoid system in human osteoclasts: possible involvement in bone formation and resorption. Bone 44(3):476–484PubMedCrossRefGoogle Scholar
  27. Santoro A, Pisanti S, Grimaldi C et al (2009) Rimonabant inhibits human colon cancer cell growth and reduces the formation of precancerous lesions in the mouse colon. Int J Cancer 125(5):996–1003PubMedCrossRefGoogle Scholar
  28. Sospedra M, Martin R (2005) Immunology of multiple sclerosis. Annu Rev Immunol 23:683–747PubMedCrossRefGoogle Scholar
  29. Van Sickle MD, Duncan M, Kingsley PJ et al (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310(5746):329–332PubMedCrossRefGoogle Scholar
  30. Zhang M, Martin BR, Adler MW et al (2009) Modulation of cannabinoid receptor activation as a neuroprotective strategy for EAE and stroke. J Neuroimmune Pharmacol 4(2):249–259PubMedCrossRefPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Anna Maria Malfitano
    • 1
    • 2
  • Chiara Laezza
    • 3
  • Giuseppe Saccomanni
    • 4
  • Tiziano Tuccinardi
    • 4
  • Clementina Manera
    • 4
  • Adriano Martinelli
    • 4
  • Elena Ciaglia
    • 1
    • 2
  • Simona Pisanti
    • 1
    • 2
  • Mario Vitale
    • 1
    • 2
  • Patrizia Gazzerro
    • 2
  • Maurizio Bifulco
    • 1
    • 2
  1. 1.Dipartimento di Medicina e ChirurgiaUniversità di Salerno Facoltà di MedicinaBaronissiItaly
  2. 2.Dipartimento di FarmaciaUniversità di SalernoFiscianoItaly
  3. 3.Istituto di Endocrinologia e Oncologia SperimentaleIEOS, CNRNapoliItaly
  4. 4.Dipartimento di FarmaciaUniversità of PisaPisaItaly

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