INHIBITION OF MEDIATOR RELEASE IN RBL-2H3 CELLS BY SOME H-1-ANTAGONIST DERIVED ANTIALLERGIC DRUGS - RELATION TO LIPOPHILICITY AND MEMBRANE EFFECTS

In a model for mucosal mast cells (RBL-2H3 cells) a set H-1-antagonist derived anti-allergic drugs containing a diphenylmethyl piperazinyl m oiety was examined for their ability to inhibit release of the mediato r beta-hexosaminidase. Cells were activated with antigen or the calciu m ionophore A23187, whether or not in combination with the phorbol est er 12-O-tetradecanoylphorbol-13-acetate (TPA). Oxatomide, hydroxyzine and cetirizine inhibit the antigen induced beta-hexosaminidase release . The release triggered by A23187, whether or not in combination with TPA is hardly influenced by the compounds. A biphasic dependence of th e inhibition of exocytosis in RBL cells on lipophilicity is observed w ith the optimum at log P is 5-6. The extremely lipophilic compounds me clozine and buclizine are not active in this model. pH dependence of t he effect of the drugs shows that especially the uncharged species are active in inhibiting exocytosis. The investigated compounds show an e ffect on phase transitions in L-alpha-phosphatidylcholine dipalmitoyl liposomes as assayed with differential scanning calorimetry (DSC). For the less extremely lipophilic compounds the induced changes in the ph ospholipid membranes increased with lipophilicity. The relation betwee n structural features of the drug and the interaction with phospholipi ds 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 aff ect several membrane related processes, which are abundant in the earl y phases of the IgE-mediated signal transduction process.