Monoamine oxidase inhibitors discovery

Monoamine—Oxidase Inhibitors. In the mid-1950s, tuberculosis patients with depression being treated with iproniazid (42) were occasionally reported to become euphoric. This observation led to the discovery of irreversible monoamine—oxidase (MAO) inhibiting properties. Hydrazine and nonhydrazine-related MAO inhibitors were subsequentiy shown to be antidepressants (122). Three other clinically effective irreversible MAO inhibitors have been approved for treatment of major depression phenelzine (43), isocarboxazid (44), and tranylcypromine (45). 

Serendipity has played a major role in the discovery of most classes of psychotropic drugs. For example, the observation that the first antidepressants, the tricyclic antidepressants and the monoamine oxidase inhibitors, impeded the reuptake of biogenic amines into brain slices, or inhibited their metabolism, following their acute administration to rats, provided the experimenter with a mechanism that could be easily investigated in vitro. Such methods led to the development of numerous antidepressants that differed in their potency, and to some extent in their side effects (for example, the selective serotonin reuptake inhibitors) but did little to further the development of novel antidepressants showing greater therapeutic efficacy. The accidental discovery of atypical antidepressants such as mianserin led to the broadening of the basis of the animal models... 

The development of specific drugs for the treatment of depression only occurred in the early 1950s with the accidental discovery of the monoamine oxidase inhibitors (MAOIs) and the tricyclic antidepressants (TCAs). This period marked the beginning of the era of pharmacopsychiatry. 

It can be argued that the introduction of lithium salts into the practice of psychiatry in 1949 heralded the beginning of psychopharmacology, as it predated the discovery of chlorpromazine, imipramine, monoamine oxidase inhibitors and resperine. Lithium came into clinical use serendipitously, the Australian psychiatrist Cade having by chance given it to a small group of manic patients and found that it had beneficial effects. 

Similar to the discovery of other psychiatric medications, the mood-enhancing effects of monoamine oxidase inhibitors (MAOIs) were identified serendipi-tously mood improvements were observed in patients with tuberculosis treated with iproniazid (Bloch et ah, 1954) The early enthusiasm for the MAOIs was based on significant and unprecedented antidepressant effects and the link between antidepressant efficacy and their... 

Panic disorder is one of the most prevalent psychiatric disorders in industrialized countries. It is often associated with agoraphobia and has an estimated prevalence of between 1% and 6%. The use of imipramine in the treatment of anxiety by Klein and Fink, and the discovery by William Sargant that monoamine oxidase inhibitors (MAOIs) were effective in the treatment of "atypical depression" over 30 years ago led to the investigation of the efficacy of such treatments in patients with panic disorder. Since that time, such drugs have been shown to attenuate the symptoms of panic in addition to those of phobic avoidance and anticipatory anxiety. As both the... 

Antidepressants were first introduced into the market in the 1950s with the serendipitous discovery of the antidepressant effect of two drugs initially evaluated for other medical uses Iproniazide, a monoamine oxidase inhibitor (MAOI), and Imipramine, a tricyclic antidepressant (TCA). Since then, a whole new generation of chemically and pharmacologically unrelated compounds have been introduced, which appear to be safer and better tolerated due to a more specific mechanism of action. These include selective serotonin reuptake inhibitors (SSRIs), serotonin and... 

The discovery of the antidepressant effect of medications was coincidental to their use for other disorders. Initial work published in 1952 reported that iproniazid (originally used for the treatment of tuberculosis) could elevate mood. Although the use of iproniazid was discontinued due to toxicity, many other additional medications have been tested and approved for the treatment of depression. These include monoamine oxidase inhibitors, tricyclics, selective serotonin reuptake inhibitors, and a heterogeneous class of atypical drugs. 

Kline, N. S. 1970, Monoamine oxidase inhibitors an unfinished picaresque tale, in Discoveries in Biological Psychiatry, F. Ayd B. Blackwell, eds, JB Lippincott Company, Philadelphia, pp. 194-204. 

The first class of antidepressants was developed in the early 1950s with the discovery of an antitubercular drug iproniazid that possesses mood-elevating properties (Nutt, 2002). Iproniazid is a monoamine oxidase inhibitor (MAOl). Monoamine oxidase is the enzyme that breaks down serotonin, dopamine, and norepinephrine. The inhibition of monoamine oxidase increases levels of monoamines in the synapse. 

After the initial discovery that 0-fluoromethylene-substituted amines (e.g., 184, Table 1) were potent, mechanism-based inhibitors of monoamine oxidase (MAO) (41), the concept was successfully broadened to include most of the common amine oxidases (Table 1). This approach was also used to design inhibitors of y-aminobutyric acid transaminase both the a- and 0- substituted amino acids 189 and 190 were found to inactivate this enzyme. Recently, applica-tion of this concept to the design of inhibitors of S-adenosyl-homocysteine hydrolase (SAH) has led to the discovery of very potent inhibitors of this enzyme (e.g., 176, Table 1). 

A different approach to Parkinsonism would be the use of inhibitors of monoamine oxidase (MAO), the enzyme that oxidatively deaminates catechol and other monamines, including DA, NE, and EP (see subsequent discussion of metabolism and other uses). Such a drug would tend to preserve brain DA and be effective itself and/or potentiate levodopa. Early attempts at such combinations produced hypertension. Subsequently, with the discovery that two MAO isozymes, A and B, exist (more discussion later), it was realized that the drugs tested were nonselective. It is now understood that MAO B primarily metabolizes DA. Selegiline (Eldepryl) appears to be a specific type B MAO inhibitor, and does extend the duration and increase the efficacy of levodopa. The drug is promising, probably as an adjunct to levodopa or in levodopa refractory patients. 

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