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Inhibition of mediator release in RBL-2H3 cells by some H1-antagonist derived anti-allergic drugs: Relation to lipophilicity and membrane effects

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Abstract

In a model for mucosal mast cells (RBL-2H3 cells) a set H1-antagonist derived anti-allergic drugs containing a diphenylmethyl piperazinyl moiety was examined for their ability to inhibit release of the mediatorβ-hexosaminidase. Cells were activated with antigen or the calcium ionophore A23187, whether or not in combination with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Oxatomide, hydroxyzine and cetirizine inhibit the antigen inducedβ-hexosaminidase release. The release triggered by A23187, whether or not in combination with TPA is hardly influenced by the compounds. A biphasic dependence of the inhibition of exocytosis in RBL cells on lipophilicity is observed with the optimum at log P is 5–6. The extremely lipophilic compounds meclozine and buclizine are not active in this model. pH dependence of the effect of the drugs shows that especially the uncharged species are active in inhibiting exocytosis. The investigated compounds show an effect on phase transitions in L-α-phosphatidylcholine dipalmitoyl liposomes as assayed with differential scanning calorimetry (DSC). For the less extremely lipophilic compounds the induced changes in the phospholipid membranes increased with lipophilicity. The relation between structural features of the drug and the interaction with phospholipids is discussed in view of the DSC results. We conclude that location of the active drugs at the membrane or the membrane/protein interface is important for the inhibiting activity on exocytosis. This could affect several membrane related processes, which are abundant in the early phases of the IgE-mediated signal transduction process.

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Abbreviations

RBL:

2H3 cells, a subline of rat basophilic leukemia cells

TPA:

12-O-tetradecanoylphorbol-13-acetate

A23187:

calcium ionophore

LDH:

lactate dehydrogenase

DSC:

differential scanning calorimetry

DPPC:

L-α-phosphatidylcholine dipalmitoyl

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Authors and Affiliations

  1. Chemical Interfaces and Thermodynamics Group, Faculty of Chemistry, Utrecht University, Padualaan 8, NL-3508 TB, Utrecht, The Netherlands

    J. C. van Miltenburg

  2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Utrecht University, P.O. Box 80082, NL-3508 TB, Utrecht, The Netherlands

    M. J. E. Fischer, J. J. C. Paulussen, D. A. Horbach, E. P. W. Roelofsen, J. C. van Miltenburg, N. J. de Mol & L. H. M. Janssen

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  1. M. J. E. Fischer
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  2. J. J. C. Paulussen
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  3. D. A. Horbach
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  4. E. P. W. Roelofsen
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  5. J. C. van Miltenburg
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  6. N. J. de Mol
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  7. L. H. M. Janssen
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Fischer, M.J.E., Paulussen, J.J.C., Horbach, D.A. et al. Inhibition of mediator release in RBL-2H3 cells by some H1-antagonist derived anti-allergic drugs: Relation to lipophilicity and membrane effects. Inflamm Res 44, 92–97 (1995). https://doi.org/10.1007/BF01793220

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  • DOI: https://doi.org/10.1007/BF01793220

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