Note. Affinity and potency = equilibrium dissociation constants in molarity. Ki = tfi-adrenergic; &2 = ® 2-adrenergic; DA = dopamine; 5 HT = serotonin; 5-HTia = serotonin1A; 5-HT2 = serotonin2; Hi = histamines Mi = muscarinic^ NE = norepinephrine.

Source. Uptake potency data adapted from Tatsumi et al. 1997. Receptor affinity data adapted from Richelson and Nelson 1984.

The nature of the central three-ring structure produces other differences. For example, amitriptyline and nortriptyline share a similar dibenzocycloheptadiene structure, although their side chains are identical to those of imipramine and desipramine, respectively. Similar to the imipramine-desipramine pair, amitriptyline and nortriptyline have similar differences in potency in blocking the serotonin and norepinephrine transporters; however, compared with imipramine, amitriptyline is more anticholinergic and antihistaminic, has greater «i-adrenergic receptor blockade, and is somewhat more potent in blocking the serotonin transporter (see Table 12-1) (Cusack et al. 1994; Richelson and Nelson 1984; Tatsumi et al. 1997).

Of the tricyclics, clomipramine is the most potent in blocking the serotonin transporter, although its metabolite desmethylclomipramine is a potent norepinephrine reuptake inhibitor (Hall and Ogren 1981). Doxepin is structurally most similar to amitriptyline but is more similar in functional potency to imipramine (Pinder et al. 1977). Doxepin is the most antihistaminic of these compounds. Protriptyline is structurally most similar to nortriptyline but is more slowly cleared (has a longer elimination half-life) and is given in doses about one-third those of nortriptyline (Moody et al. 1977).

The structure of amoxapine differs from the structures of the other tricyclics. With a central three-ring structure and a side chain that differ from those of the tricyclics, amoxapine is structurally more similar to the neuroleptic loxapine, from which it is derived. Similar to the secondary tricyclics, it is a potent norepinephrine reuptake inhibitor. Unlike all of the other compounds in this group, amoxapine, and particularly its metabolite 7-hydroxyamoxapine, blocks postsynaptic dopamine receptors (Coupet et al. 1979). As a result, it is the only compound in the group that has antipsychotic activity in addition to antidepressant effects.

Maprotiline also differs from the others in this group. Although maprotiline is referred to as a heterocyclic or tetracyclic, these terms do not explain its inclusion in the group. The side chain, however, is identical to that in desipramine, nortriptyline, and protriptyline. As would be predicted from this similarity, maprotiline is most potent in blocking the norepinephrine transporter (Randrup and Braestrup 1977).

As discussed below, it is important to remember that in humans, the tertiary tricyclic compounds are demethylated to secondary tricyclic compounds, all of which are potent norepinephrine reuptake inhibitors. As a result, when these tertiary compounds are administered to human subjects, the effects of both the metabolite and the parent have to be taken into account.

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