Antidepressant drugs, Tetracyclic

A Single Comprehensive Gas Chromatographic Assay for Tricyclic and Tetracyclic Antidepressant Drugs and Their Major Metabolites in Plasma... 

Cycloaddition of nitrone (26) to allylamine (538) leads to the synthesis of chiral tetracyclic isoxazolidine (539) which is used in the preparation of compound R107500. This compound has been found to be active as an antiolytic and antidepressant. It also has the potential to inhibit drug abuse (Scheme 2.252) (80). 

Maprotiline is frequently referred to as a tetracyclic antidepressant. This hybrid drug, containing both elements of classic tricyclic antidepressants and protriptyline elements, is pharmacologically and clinically more similar to imipramine. 

Mianserin and its analogue, mirtazapine (i.e., 6-azo-mianserin), are tetracyclic compounds and differ from other antidepressants in terms of the putative mechanism responsible for their antidepressant efficacy (171). Mianserin is the older drug and is marketed in several countries around the world but not in the United States. 

Many chromatographic separations of isotopologues of various amines that are biologically active or have drug properties have been achieved. Among these are perdeuteronucleosides 137 a tetracyclic 3,3,4,4-c/4-piperazine with antimigraine activity 138 the tetracyclic antidepressant mianserin with 2H or 3H in the A-methyl 139 A-CH3-tritiated chlorpromazine... 

Trimipramine is a sedating tricyclic antidepressant that has been used as a hypnotic (1) it shares this activity with other drugs of its class, notably amitriptyline, dosulepin, doxepin, and trazodone, and with the tetracyclics mianserin and mirtazapine. Trimipramine may be preferred for this purpose, since it has less effect on sleep architecture, including REM sleep (2), and has only a modest propensity to produce rebound insomnia in a subset of patients (3). Sedative antidepressants may be particularly appropriate for individuals at risk of benzodiazepine abuse and patients with chronic pain (4). The usual pattern of tricyclic adverse effects, especially antimuscarinic and hypotensive effects and weight gain, can be expected. Some authors, enthusiastic about GABA enhancers, contend that antidepressants are not useful hypnotic alternatives (5). 

Mirtazapine is a tetracyclic antidepressant, similar to mianserin, and is a potent 5-HT2a/2c receptor antagonist. It has been successfully used to treat akathisia. In a doubleblind, placebo-controlled study in 26 patients with schizophrenia who were receiving neuroleptic drugs, mirtazapine 15 mg/day for 5 days was associated with less akathisia (227). 

If this option is elected, start the MAOl with the tricyclic/tetracyclic antidepressant simultaneously at low doses after appropriate drug washout, then alternately increase doses of these agents every few days to a week as tolerated... 

Although very strict dietary and concomitant drug restrictions must be observed to prevent hypertensive crises and serotonin syndrome, the most common side effects of MAOl and tricyclic/tetracyclic antidepressant combinations may be weight gain and orthostatic hypotension... 

Adverse drug reacfions can resulfs from combining MAO inhibitors with tricyclic/tetracyclic antidepressants and related compounds, including carbamazepine, cyclobenzaprine, and mirtazapine, and should be avoided except by experts to treat difficult cases (see Pearls)... 

No pharmacokinetic interactions or elevations in plasma drug levels of tricyclic or tetracyclic antidepressants when adding or switching to or from milnacipran... 

Indeed, on the basis of the cyclase assay, amitriptyline is one of the most potent H2-antagonists presently available (KD 0.05 /iM) [ 181, 193]. The dissociation constants for many of the antidepressants are sufficiently low to suggest that the activation of adenylate cyclase by histamine may be inhibited by therapeutically effective concentrations of these compounds [81, 193]. This biochemical action of the tricyclic and tetracyclic antidepressants may thus represent part of the molecular basis of clinical antidepressant activity [193]. It should also be noted that most tricyclic and tetracyclic antidepressants are much more potent inhibitors of H,-receptor responses [67, 120] than they are of the H2-cyclase response, and this property of these compounds may mediate the sedative actions of these drugs [71, 73, 75]. 

With its 2-carbon bridge across the middle, maprotiline (Fig. 12-26) is technically a tetracyclic compound, yet it behaves as a secondary amine TCA (i.e., a relatively selective NE reuptake). The drug s second-generation standing is purely chronological. It has been in the U.S. market since 1981. Amoxapine, which was marketed the same year, is, of course, the N4-demethylated antipsychotic loxapine (Fig. 12-26). It has been suggested the cumulation of the 8-OH metabolite may be responsible for the inhibition of NE uptake and account for the antidepressant effect. Nomifensine, which is a tetrahydroisoquinoline with potential as an inhibitor of NE and DA, but not 5-HT, was withdrawn in 1987 for toxicity reasons. 

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