Iminium Ions

Mianserin is a tetracyclic antidepressant that causes agranulocytosis in isolated cases in patients. Detailed structural analysis [20] has indicated that oxidation by cytochrome P450 to one or more iminium ions is the likely causative first step in this toxicity, the most likely being the C4-N5 version (Figure 8.19). Evidence for this is provided by the C14p methyl and the 010 analogues which cannot form the corresponding nitrenium and carbonium ions, but are cytotoxic. Removal of the N5 nitrogen atom in analogous structures abolishes production of the reactive metabolites (Figure 8.20).

Fig. 8.19 Structures of mianserin (A) with N5 shown and its putative reactive metabolites: N5-C14p iminium ion (B), C4-N5 iminium ion (C) and carbonium ion at C10 (D). Evidence indicates that metabolite B is the causative agent.

Fig. 8.20 Structures of mianserin analogues. A and B cannot form the N5-C14b iminium and C10 carbonium ion but are still toxic. C without the N5 nitrogen is not toxic implicating the C4-N5 iminium ion.

Fig. 8.20 Structures of mianserin analogues. A and B cannot form the N5-C14b iminium and C10 carbonium ion but are still toxic. C without the N5 nitrogen is not toxic implicating the C4-N5 iminium ion.

Vesnarinone is a drug used to treat congestive heart failure and is associated with a 1 % incidence of agranulocytosis. When metabolized by activated neutrophils the major metabolite is veratrylpiperazinamide (Figure 8.21). This unusual N-dealkyla-tion (of an aromatic ring) can be rationalized by chlorination of the nitrogen to which the aromatic ring is attached by HOCl, followed by the loss of HCl to form the reactive imminium ion, which itself can react with nucleophiles. Hydrolysis of the iminium ion yields veratrylpiperazinamide and another reactive species, the quinone imine (see Section 8.3).

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