Competitive inhibition of 48/80-induced histamine release by benzalkonium chloride and its analogs and the polyamine receptor in mast cells.

Benzalkonium Cl is a family of benzyldimethylalkylammonium compounds which are selective inhibitors of histamine release induced by 48/80 and many other polyamines, but do not inhibit histamine release caused by antigen-antibody reactions, ionophores, enzymes or detergents. In this study, additional histamine-releasing poly- and monoamines found to be antagonized by benzalkonium Cl in rat mast cells were cadaverine, hexamethonium, decamethonium, lysine, dilysine, trilysine, pentalysine, mellitin, pentamidine, spermidine, spermine, morphine, norepinephrine and tyramine. Benzyldimethyltetradecylammonium Cl, one of the safest and most potent members of the benzalkonium Cl family, was found to antagonize 48/80-induced histamine release by a competitive mechanism. Benzyldimethyltetradecylammonium Cl was also found to inhibit 48/80-induced histamine release from mast cells of the hamster in vitro and in the rat, cat and mongoose in vivo. Structure-activity relations studies revealed that: 1) substitution of alkyl, cycloalkyl or other aryl groups for the benzyl group of benzyldimethyltetradecylammonium Cl reduced activity only slightly; 2) demethylation to form the tertiary or secondary amines dramatically reduced activity; 3) optimal length of the alkyl side chain was usually 12 to 14 carbons; and 4) replacement of the nitrogen with phosphorus or sulfur did not significantly alter activity. It appears that the polyamine receptor on mast cells is: 1) widespread in mammals; 2) stimulated by a broad range of polyamines and some monoamines; 3) responsive both in vitro and in vivo; and 4) competitively antagonized by a fairly diverse family of inhibitors possessing a permanent positive charge attached to a substantial but limited hydrophobic moiety.