FIGURE 4.52 Mechanism for formation of the 4-imidazolidinone from the carbinolamine metabolic intermediate of lidocaine.
N-Dealkylation reactions are not restricted to tertiary amines. Secondary amines as well as primary amines can also be dealkylated although both types are less favored than tertiary amines. In the case of primary amines, the lone pair of electrons of the amino group can interact and complex with the Fe3+ of heme. Thus primary amines tend to be inhibitors of P450 activation and for that reason are generally poor substrates. Secondary amines have metabolic properties intermediary between those of tertiary amines and primary amines. They are less-effective inhibitors because of increased steric hindrance to complex formation but are also better substrates because they are less-effective inhibitors and thereby increase the effective concentration of enzyme.
The alkyl substituents of the amino group need not be primary to be susceptible to oxidative removal. They can be secondary like the isopropyl group of propranolol (Fig. 4.53) in which case the carbinolamine dissociates into a ketone (acetone) and a primary amine.
N-dealkylation and deamination reactions are the same reaction. For example, in the metabolism of propranolol, if oxidation occurs to the left of the nitrogen the reaction is called deamination because the nitrogen is lost from the larger part of the molecule, whereas if the oxidation occurs to the right of the nitrogen it is called a N-dealkylation because the alkyl group is removed from the nitrogen; however, the basic mechanisms of these two reactions are identical. If the two groups attached to the nitrogen were of equal size, it would be completely arbitrary whether it would be called N-dealkylation or deamination.
The disassociation of a carbinolamine is reversible, but in a biological system, when a carbinolamine dissociates to an amine and an aldehyde or ketone, these products diffuse away from each other and the dissociation is essentially irreversible. However, if the amine
Was this article helpful?