Tricyclic secondary amine antidepressants

Doxepin [1668-19-5] (38), unlike other commercially available tricyclics, has an oxygen atom in the bridge between the two aromatic rings. It is marketed as a cis—trans mixture (1 5) of isomers, both of which are active. This close relative of amitriptyline (33) has both sedative and anxiolytic properties associated with its antidepressant profile. Maprotiline [10262-69-8] (39) and amoxapine [14028-44-5] (40) are pharmacologically, although not chemically, similar to the tricyclic secondary amines. Clomipramine [303-49-1] (41) has similar pharmacological and antidepressant efficacy. However, clomipramine is approved by the U.S. FDA only for the treatment of obsessive—compulsive disorder. Representative brands of tricyclic antidepressants marketed in the United States are Us ted in Table 2. 

Tricyclic Antidepressants (TCAs). The TCAs, particularly imipramine (Tofranil), were also discovered soon after their introduction to be effective in the treatment of panic attacks. Imipramine, the best-studied TCA in the treatment of panic disorder, is most often helpful at daily doses of 150-250 mg, though it must be started at 10-25 mg, usually at bedtime, and gradually increased over 2-4 weeks. Although they are not as well studied, many clinicians prefer to use the secondary amine TCAs, desipramine (Norpramin) and nortriptyline (Pamelor), because they have milder side effects than imipramine. Clomipramine (Anafranil), though probably the TCA with the greatest side effect burden, is often said to be most effective in patients with refractory disease. 

As noted earlier, most classical antidepressant agents consist of propylamine derivatives of tricyclic aromatic compounds. The antidepressant molecule tametraline is thus notable in that it is built on a bicyclic nucleus that directly carries the amine substituent. Reaction of 4-phenyl-l-tetralone (18) (obtainable by Friedel-Crafts cyclization of 4,4-diphenyl butyric acid) with methyl amine in the presence of titanium chloride gives the corresponding Schiff base. Reduction by means of sodium borohydride affords the secondary amine as a mixture of cis (21) and trans (20) isomers. The latter is separated to afford the more active antidepressant of the pair, tametraline (20). 

It is believed that tricyclic antidepressants inhibit the (neuronal) reuptake of norepinephrine (noradrenaline) and/or serotonin by presynaptic nerve endings, thus blocking one of the leading mechanisms of their inactivation, and thereby increasing the concentration of the indicated amines potentiating their effects. It should be noted that, as a rule, secondary amines, which are representatives of tricyclic antidepressants, exhibit high activity, blocking the neuronal reuptake of norepinephrine, while tertiary amines act more on the neuronal reuptake of serotonin. 

Tricyclic antidepressants (TCAs) modulate various brain neurotransmitters, especially norepinephrine and serotonin, by blocking reuptake presynaptically. The secondary amines (desipramine, nortriptyline) are more selective for noradrenergic function and have less side effects in sensitive populations. Advantages of this class of drugs include their relative long half life (approximately 12 hours), absence of abuse potential, and putative positive effects on mood and anxiety, sleep, and tics. 

The latency period of weeks or even months that occurs between the initiation of therapy and the antidepressant effect when tertiary tricyclics are used. Secondary amines act faster, but in both cases, although elevated neurotransmitter levels become rapidly apparent, the clinical improvement lags far behind. 

Partly reduced counterparts of the indole nucleus provide the basis for several agents with varied biological activities. A pair of closely related A-phenyl derivatives have both shown antidepressant activity in test systems. The apparent preference for the monomethyl amine suggests that these act by the same mechanism as the classical tricyclic antidepressants, where the secondary amine is the more active species. The first step in the preparation of the common intermediate (27-3) to these compounds consists of acylation of diphenylamine (27-1) with chloroacetyl chloride. 

FIGURE 6—11. Certain tricyclic antidepressants, especially secondary amines such as clomipramine and imipramine, are substrates for CYP450 1A2. This enzyme converts the tricyclics into active metabolites by demethylation to form desmethylclomipramine and desipramine, respectively. 

One CYP450 enzyme of relevance to antidepressants is 1A2 (Figs. 6—11 and 6—12). Certain tricyclic antidepressants (TCAs) are substrates for this enzyme, especially the secondary amines such as clomipramine and imipramine (Fig. 6—11). CYP450 1A2 demethylates such TCAs, but does not thereby inactivate them. In these cases, the desmethyl metabolite of the TCA (e.g., desmethylclomipramine and desipramine) is still an active drug (Fig. 6—12). 

Tricyclic antidepressants, like some of the phenothiazine derivatives, are sedative in nature. Those compounds containing a tertiary amine (imipramine, amitriptyline, and doxepin) are the most sedative. Those compounds containing a secondary amine (nortriptyline and desipramine) are less so, and protriptyline has no sedative effect. 

N. Narsimhachari and R. O. Friedel, N.-Alkylation of secondary amine tricyclic antidepressants by GC-MS-MS technique, Anal. Lett., 725 77(1979). 

Way BA, Stickle D, Mitchell ME et al (1998) Isotope dilution gas chromatographic-mass spectrometric measurement of tricyclic antidepressant drugs. Utility of the 4-carbethoxyhexafluorobutyryl derivatives of secondary amines. J Anal Toxicol 22 374-382... 

Tricyclic antidepressants Greater sensitivity to anticholinergic effects, arrhythmic effects Preference for desipramine, nortriptyline (better tolerated secondary amines)... 

The increase in tricyclic concentrations following valproate is probably partly due to inhibition of CYP2C isozymes, preventing demethylation of tertiary tricyclic antidepressants to the corresponding secondary amines (desmethylimipramine in the case of clomipramine). However, valproate can also increase the plasma concentrations of secondary amine tricyclics, such as nortriptyline (183). The current data suggest that the combined use of tricyclic antidepressants and valproate should be undertaken with caution. 

The tricyclic antidepressants typically undergo multiple routes of metabolism. The most common, depending on the particular ring system, are N-demethylation of the terminal amine, aromatic hydroxylation, and benzylic or "bridge" hydroxylation (see Table 8.7). In general, with the exception of the secondary amine metabolites of iV AT-dimethyl-amino TCAs, the metabolites are usually less active or inactive as antidepressants. 

Tricyclic amine antidepressants (TCAs) are nonselective5-HT and NE reuptake inhibitors. Two TCAs, imipramine (20) and desi-pramine (21), are used to treat bulimia nervosa, primarily as second-line therapies. Imipramine, a tertiary amine, is a 5-HT re-uptake inhibitor with weak NE reuptake activity. Desipramine, a secondary amine and the des-ethyl analog of imipramine, is a NE reuptake inhibitor. Other TCAs used less frequently to treat BN include amitriptyline (22) and its N-desmethyl analog nortripyline (23). 

Thus there appear to be significant mechanistic differences the hydrazines inhibit MAO, the tertiary amine tricyclics seem to inhibit the serotonin amine pump, whereas the secondary amine ones seem better in switching off the NE reuptake mechanism. Table 12-18, however, shows that there is some overlap. Nevertheless, there is a thread of commonality—the net increase of amine neurotransmitters in the synaptic area—yet all these drugs require several weeks of treatment before objective results are noted. The biogenic amine hypothesis does not satisfactorily explain this. It is even more difficult to explain the antidepressant action of some of the second-generation drugs, such as mianserin (Fig. 12-26), that seem to have no significant effect on amine reuptake mechanism of either... 

With some notable exceptions, inactivation and elimination of most antidepressants occurs over a period of several days. Generally, secondary-amine tricyclic antidepressants and the N-demethylated derivatives of serotonin reuptake inhibitors have elimination half-lives about twice those of the parent drugs. Nevertheless, most tricyclics are almost completely eliminated within 7 to 10 days. An exceptionally long-acting tricyclic antidepressant is protriptyline (half-hfe of about 80 hours). Most MAO inhibitors are long acting because recovery from their effects requires the synthesis of new enzyme over a period of 1 to 2 weeks. 

Table 21.4. Common Side Effects with Secondary Amine Tricyclic Antidepressants and Recommendations...

---