COMPETITIVE-INHIBITION OF 48/80-INDUCED HISTAMINE-RELEASE BY BENZALKONIUM CHLORIDE AND ITS ANALOGS AND THE POLYAMINE RECEPTOR IN MAST-CELLS

  • 1 January 1982
    • journal article
    • research article
    • Vol. 222  (3) , 652-657
Abstract
Benzalkonium chloride [BAC] 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. Additional histamine-releasing poly- and monoamines which were antagonized by BAC in rat mast cells were cadaverine, hexamethonium, decamethonium, lysine, dilysine, trilysine, pentalysine, melittin, pentamidine, spermidine, spermine, morphine, norepinephrine and tyramine. Benzyldimethyltetradecylammonium chloride [BDTA], one of the safest and most potent members of the BAC family, antagonized 48/80-induced histamine release by a competitive mechanism. BDTA also inhibited 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 the following: substitution of alkyl, cycloalkyl or other aryl groups for the benzyl group of BDTA reduced activity only slightly; demethylation to form the tertiary or secondary amines dramatically reduced activity; optimal length of the alkyl side chain was usually 12-14 carbons; and replacement of the N with P or S did not significantly alter activity. It appears that the polyamine receptor on mast cells is widespread in mammals, stimulated by a broad range of polyamines and some monoamines, responsive both in vitro and in vivo, and competitively antagonized by a fairly diverse family of inhibitors possessing a permanent positive charge attached to a substantial but limited hydrophobic moiety.