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.

Xylamine (N-2'-chloroethyl-N-ethyl-2-methylbenzylamine), a nitrogen mustard that irreversibly inhibits norepinephrine uptake, cyclizes in solution to form an aziridinium ion. The first-order rate constants for cyclization at 23 degrees and 37 degrees are 0.12 min-1 and 0.40 min-1, respectively. The aziridinium ion is relatively stable at 23 degrees but hydrolyzes at 37 degrees 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 norepinephrine 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 sodium-dependent. The dimer was a weak competitive inhibitor of norepinephrine uptake, with an IC50 of about 10 microM. The 2-hydroxyethylamine, at 100 microM, competitively inhibited only 20% of control norepinephrine accumulation. These results demonstrate that the aziridinium ion is responsible for xylamine's uptake blocking activity and that the other xylamine derivatives do not influence this action.