Antidepressant drugs structure-activity

Iprindol (25) is yet another antidepressant drug that differs structurally from the classical tricyclic antidepressants. Condensation of phenylhydrazine and cyclooctanone by the Rogers-Corson modification of the Fischer indole synthesis affords the tricyclic intermediate, 24. The active hydrogen of 6,7,8,9,10-hexahydro-5H-cyclooct[b]indole (24) is removed by reaction with sodium metal in DMF and the resulting salt condensed with 3-dimethylaminopropyl chloride. There is thus obtained iprindol (25). ... 

The phenothiazines, such as chlorpromazine, used in the treatment of schizophrenia, the tricyclic antidepressant drugs such as imipramine and amitryp-tUine, antimalarials such as quinacrine, and the anticancer agent adriamycin are structural analogs of riboflavin (see Figure 7.6) and inhibit flavokinase. In experimental animals, administration of these drugs at doses equivalent to those used clinically results in an increase in the EGR activation coefficient (Section 7.5.2) and increased urinary excretion of riboflavin, with reduced tissue concentrations of riboflavin phosphate and FAD, despite feeding diets providing more riboflavin than is needed to meet requirements (Pinto et al., 1981). 

Side Effects a.nd Toxicity. Adverse effects to the tricyclic antidepressants, primarily the result of the actions of these compounds on either the autonomic, cardiovascular, or central nervous systems, are summarized in Table 3. The most serious side effects of the tricyclics concern the cardiovascular system. Arrhythmias, which are dose-dependent and rarely occur at therapeutic plasma levels, can be life-threatening. In order to prevent adverse effects, as well as to be certain that the patient has taken enough drug to be effective, the steady-state semm levels of tricyclic antidepressant dmgs are monitored as a matter of good practice. A comprehensive review of structure—activity relationships among the tricyclic antidepressants is available (42). 

The effect of this structural hybrid formation was an antidepressant drug with tranquilizing and antianxiety properties (59). The drug was most effective in neurotic depressions and of little value in psychotic depressive reactions (59, 85). Its activity range would thus appear to be between imi-pramine and meprobamate (85). Side effects were minimal with this drug and its onset of action occurred within 1 to 2 days (81). Hence, the drug is particularly useful in the treatment of ambulatory patients. 

The MAO inhibitor tranylcypromine is amphetamine-like in structure but interacts only weakly at DA transporters. The phenylpiperazine nefazodone, and to a lesser extent, the structurally related trazodone have weak inhibitory actions on 5-HT transport nefazodone also may have a minor effect on NE transport. This agent also has a prominent direct antagonistic effect at S-HT receptors that may contribute to antidepressant and anxiolytic activity. Both drugs also may inhibit presynaptic 5-HTj subtype autoreceptors to enhance neuronal release of 5-HT, though they probably also exert at least partial-agonist effects on postsynaptic 5-HTj receptors. Trazodone also blocks cerebral and Hj receptors, possibly contributing to its tendency to induce priapism and sedation, respectively. 

These enzymes are highly susceptible to inactivation by y3,y-acetylenic amines. Flavin-linked mitochondrial monoamine oxidase is irreversibly inhibited by the antidepressant drug pargyline. Structure activity studies have shown that the acetylenic unit is crucial and that it has to be /3,y to the nitrogen. ... 

DIBENZOCYCLOHEPTANES AND DIBENZOCYCLOHEPTENES Drugs in this structural class have effected a revolution in the treatment of severely depressed patients such that deinstitutionalization is a feasible public policy. The compounds often show other CNS activities which depend on the length of the side chain. One-carbon chains generally lead to anticonvulsant activity amines separated from the nucleus by three carbons usually donvey antidepressant activity. Selected examples possess significant anticholinergic activity. 

Two rather broad structural classes account for the large majority of drugs that have proven useful in the clinic for treating depression. Each of these has associated with it some clearly recognized side effects the monoamine oxidase inhibitors, most commonly derivatives of hydrazine, tend to have undesirable effects on blood pressure the tricyclic compounds on the other hand may cause undesirable changes in the heart. Considerable effort has thus been expended toward the development of antidepressants that fall outside those structural classes. An unstated assumption in this work is the belief that very different structures will be associated with a novel mechanism of action and a different set of ancillary activities. One such compound, trazodone... 

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