Monoamine oxidase inhibitor structure

J. Wouters, F. Moureau, G. Vercauteren, G. Evrard, F. Durant, J.J. Koenig, F. Ducrey, F.X. Jarreau, Experimental and theoretical study of reversible monoamine oxidase inhibitors Structural approach of the active site of the enzyme, J. Neural. Transm. Suppi. 41 (1994) 313-319. 

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... 

Mclsaac, W., Estevez, V. Structure-action relationship of beta-carbolines as monoamine oxidase inhibitors. Biochem. Pharmacol. 15 1625, 1966. 

Martin, M., F. Sanz, M. Campillo, L. Pardo, J. Perez, and J. Turmo. 1983b. Quantum Chemical Structure Activity Relationships on (3-carbolines as Natural Monoamine Oxidase Inhibitors. Int. J. Quant. Chem. 23, 1643. 

Figure 7.1, Structural formulae of some monoamine oxidase inhibitors (moclobemide, pirlindole and toloxatone) and alpha2 adrenoceptor antagonists [S-...

I. J. Koenig, F.X. Jarreau, A reversible monoamine oxidase inhibitor, toloxatone structural and electronic properties, Eur. J. Med. Chem. 27 (1992) 939-948. 

Therapeutic Function Antidepressant, Monoamine oxidase inhibitor Chemical Name 4-Pyridinecarboxylic acid 2-(l-methylethyl)hydrazide Common Name -Structural Formula ... 

A mechanism of irreversible toxicity of/wnz-chloroamphetamine (PC A, 120a) to serotonergic neurons has recently been proposed. According to this proposal, PCA induces 5HT release from serotonergic neurons. The ability of PCA also to function as a monoamine oxidase inhibitor leads to an accumulation of extraneuronal 5HT. Nonenzymatic oxidation produces the neurotoxin, 6-hydroxy-5HT, which is taken up into the neuron where cross-linking to macromolecular structures leads to neuronal destruction221,222. 

Anorectic drugs, which are structurally related to the amphetamines, act mainly on the satiety centre in the hypothalamus and also increase general physical activity (1). All of them, except fenfluramine, stimulate the central nervous system and can cause restlessness, nervousness, irritabihty, and insomnia. Adverse effects also occur through sympathetic stimulation and gastrointestinal irritation. Drug interactions can occur with monoamine oxidase inhibitors. Dexamfetamine, phenmetrazine, and benzfetamine can cause dependence. Some of them have been associated with cardiac valvulopathy and primary pulmonary hypertension (2). 

Anorectic drugs act mainly on the satiety centre in the hypothalamus (1). They also have metabohc effects involving fat and carbohydrate metaboUsm. Most of them are structurally related to amfetamine and increase physical activity. Their therapeutic effect tends to abate after some months, and part of this reduction in effect may be due to chemical alterations in the brain. Fenfluramine commonly produces drowsiness in normal doses, but has stimulaut effects in overdosage. Dexamfetamine, phenmetrazine, and benzfetamine all tend to cause euphoria, with a risk of addiction. Euphoria occasionally occurs with amfepramone (diethylpropion), phentermine, and chlorphentermine, but to a much lesser extent. Some adverse effects are due to sympathetic stimulation and gastrointestinal irritation these may necessitate withdrawal but are never serious. There are interactions with monoamine oxidase inhibitors and antihypertensive drugs. 

Norinder, U., Florvall, L. and Ross, S.B. (1994). A PLS Quantitative Structure-Activity Relationship Study of Some Monoamine Oxidase Inhibitors of the Phenyl Alkylamine Type. Ear. J.Med.Chem.,29,191-195. 

Chemicae Structure Phenelzine is the prototype monoamine oxidase inhibitor... 

The antidepressant drugs are generally classified according to their chemical structure (e.g., tricyclic antidepressants [TCA]) or according to their pharmacological action (e.g., monoamine oxidase inhibitors [MAOI] serotonin reuptake inhibitors [SSRI]). Certain other antidepressants, which do not fall into the above categories, are sometimes referred to as atypical antidepressants (see below). 

Functionalized oxadiazoles have received considerable attention in the pharmaceutical industry as heterocyclic amide and ester isosteres [95]. Oxadiazoles have been employed in the design of biologically active templates, e. g. core structures for muscarinic agonists, kinase inhibitors, anti-inflammatory agents, histamine H3 antagonists, monoaminic oxidase inhibitors, etc. 

Imipramine, a substance with a structure similar to the phenothiazines (Figure 5) but varying in that the ring is a dibenzazepine rather than a phenothiazine, was the first active antidepressant of the nonmomoamine oxidase inhibitor series of agents. It, like the monoamine oxidase inhibitors, is effective in less than half the patients treated. Its mode of action is not clearly understood, but there is increasing evidence that it too exerts an effect on catechol amine metabolism (19). Although serious toxic effects have been uncommon, excitement, jaundice, and blood dyscrasias have occurred (17). 

Diphenoxylate is an opiate (schedule V) with antidiarrheal properties. It is usually dispensed with atropine and sold as Lomotil. The atropine is added to discourage the abuse of diphenoxylate by narcotic addicts who are tolerant to massive doses of narcotic but not to the CNS stimulant effects of atropine. Diphenoxylate shonld be used cautiously in patients with obstructive jaundice because of its potential for hepatic coma, and in patients with diarrhea cansed by pseudomembranous colitis because of its potential for toxic megacolon. In addition, it should be used cautiously in the treatment of diarrhea caused by poisoning or by infection by Shigella, Salmonella, and some strains of E. coli because expulsion of intestinal contents may be a protective mechanism. Diphenoxylate should be used with extreme caution in patients with impaired hepatic function, cirrhosis, advanced hepatorenal disease, or abnormal liver function test results, because the drug may precipitate hepatic coma. Because diphenoxylate is structurally related to meperidine, it may cause hypertension when combined with monoamine oxidase inhibitors. As a narcotic, it will augment the CNS depressant effects of alcohol, hypnotic-sedatives, and numerous other drugs, such as neuroleptics or antidepressants that cause sedation. 

Tricyclic antidepressants are commoniy taken in overdose by suicidal patients and represent a major cause of poisoning hospitaiizations and deaths. Currently available tricyclic antidepressants are described in Table 11-7. Amitriptyline is also marketed in combination with chlordiazepoxide (Limbitrol ) or perphenazine (Etrafon or Tria-viF ). Cyclobenzaprine (FlexerilTW), a centrally acting muscle relaxant (see p 339), is structurally related to the tricyclic antidepressants but exhibits minimal cardiotoxic and variable CNS effects. Newer, noncyclic antidepressants are discussed on p 88. Monoamine oxidase inhibitors are discussed on page 269. 

Tranylcypromine is a chiral monoamine oxidase inhibitor used in the treatment of depression. The drug is similar to mefloquine in that it is contains a diastereomeric structure but is only administered as the 50 50 combination of the (- -)-lS,2R and (—)-lR,2S species. The enantiomers possess differences in their pharmacological properties in that (-I-) tranylcypromine is much more effective than its antipode in MAO inhibition, but the (—) enantiomer causes greater diminution of catecholamine reuptake and release than (-I-) enantiomer [147]. With respect to its pharmacokinetics (Table 1), the (-I-) enantiomer seemed to be cleared via the oral route 4 to 8 times more rapidly than antipode based on significantly... 

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