Imipramine hydrochloride, 5-[3-(dimethylamino)propyl]-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride (Tofranil), is the lead compound of the TCAs. It is also a close relative of the antipsychotic phenothiazines (replace the 10-11 bridge with sulfur, and the compound is the antipsychotic agent promazine). It has weaker D2 postsynaptic blocking activity than promazine and mainly affects amines (5-HT, NE, and DA) via the transporters. As is typical of dimethyl-amino compounds, anticholinergic and sedative (central H1 block) effects tend to be marked. The compound per se has a tendency toward a high 5-HT-to-NE uptake block ratio and probably can be called a serotonin transport inhibitor (SERTI). Metabolic inactivation proceeds mainly by oxidative hydroxylation in the 2-position, followed by conjugation with glucuronic acid of the conjugate. Urinary excretion predominates (about 75%), but some biliary excretion (up to 25%) can occur, probably because of the large nonpolar grouping. Oxidative hydroxylation is not as rapid or complete as that of the more nucleophilic ring phenothiazine antipsychotics; consequently, appreciable N-demethylation occurs, with a buildup of norimipramine (or desimipramine).
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