Nitrenium Ions

Clozapine, an antipsychotic agent, has the potential to cause agranulocytosis with an incidence of 1 %. The major oxidant in human neutrophils, HOCl, oxidizes clozapine to a nitrenium ion (Figure 8.17) in which the positive charge is highly delocal-ized. This metabolite is capable of binding irreversibly to the neutrophil [17]. A variety of cells including liver, neutrophils and bone marrow can form reactive clozapine metabolites which react to form glutathione thioether adducts [18].

Fig. 8.17 Structures of clozapine and its nitrenium ion, the postulated reactive metabolite generated by oxidation.

Fig. 8.17 Structures of clozapine and its nitrenium ion, the postulated reactive metabolite generated by oxidation.

Various analogues have been investigated indicating that the nitrogen-bridge between the two aromatic rings is the target, at least for HOCl oxidation. When alter-

Fig. 8.18 Alternative structures which will not generate the nitrenium ion observed with clozapine.

native bridging heteroatoms are used (Figure 8.18) similar reactive metabolites are not observed [19].

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