CHEMICAL-TRANSFORMATIONS OF XYLAMINE (N-2'-CHLOROETHYL-N-ETHYL-2-METHYLBENZYLAMINE) IN SOLUTION - PHARMACOLOGICAL ACTIVITY OF THE SPECIES DERIVED FROM THIS IRREVERSIBLE NOREPINEPHRINE UPTAKE INHIBITOR

  • 1 January 1982
    • journal article
    • research article
    • Vol. 21  (2) , 380-386
Abstract
Xylamine (N-2''-chloroethyl-N-ethyl-2-methylbenzylamine), a nitrogen mustard that irreversibly inhibits norepinephrine [NE] uptake, cyclizes in solution to form an aziridinium ion. The 1st-order rate constants for cyclization at 23 and 37.degree. C are 0.12 and 0.40 min-1, respectively. The aziridinium ion is relatively stable at 23.degree. C, but hydrolyzes at 37.degree. C with a half-time of 70 min. A dimeric compound was indirectly shown to form at 1 mM xylamine through a reaction between the parent mustard and its aziridinium ion. A similar reaction between the 2-hydroxyethylamine and the aziridinium ion does not take place at pH 7.4. The aziridinium ion, its hydrolysis product and the dimer were synthesized to evaluate directly their effects on NE uptake in rabbit thoracic aorta. The aziridinium ion was as potent as xylamine as an irreversible uptake inhibitor, and the effects of both compounds were Na-dependent. The dimer was a weak competitive inhibitor of NE uptake, with an IC50 [median inhibitory concentration] of .apprx. 10 .mu.M. The 2-hydroxyethylamine, at 100 .mu.M, competitively inhibited only 20% of control NE accumulation. The aziridinium ion is responsible for xylamine''s uptake blocking activity and the other xylamine derivatives do not influence this action.

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