Monoamine oxidase inhibitors applications

The process of oxidative deamination is the most important mechanism whereby all monoamines are inactivated (i.e. the catecholamines, 5-HT and the numerous trace amines such as phenylethylamine and tryptamine). Monoamine oxidase occurs in virtually all tissues, where it appears to be bound to the outer mitochondrial membrane. Whereas there are several specific and therapeutically useful monoamine oxidase inhibitors, inhibitors of catechol-O-methyltransferase have found little application. This is mainly due to the fact that at most only 10% of the monoamines released from the nerve terminal are catabolized by this enzyme. The main pathways involved in the catabolism of the catecholamines are shown in Figure 2.16. 

In an early study, Insel et al. [1983b] compared the efficacy of CMI with that of clorgiline, a monoamine oxidase-A inhibitor, in a controlled crossover study of patients with OCD. Although CMl was effective, patients on clorgiline did not improve at all. Vallejo et al. [1992] conducted a controlled clinical trial of the efficacy of CMl and phenelzine in 30 patients with OCD. The authors reported improvement in both groups however, the lack of a placebo control and the small size of the study groups limit the applicability of these findings. Further studies on the therapeutic role of monoamine oxidase inhibitors in OCD, especially in OCD with comorbid panic disorder, are warranted. 

Plasma levels of doxepin similar to those achieved during oral therapy may be obtained with topical application the usual drug interactions associated with tricyclic antidepressants may occur. Therefore, monoamine oxidase inhibitors must be discontinued at least 2 weeks prior to the initiation of doxepin cream. Topical application of the cream should be performed four times daily for up to 8 days of therapy. The safety and efficacy of chronic dosing has not been established. Adverse local effects include marked burning and stinging of the treatment site which may necessitate discontinuation of the cream in some patients. Allergic contact dermatitis appears to be frequent, and patients should be monitored for symptoms of hypersensitivity. 

Practical applications include the synthesis of rran5-2-phenylcyclopropanamine (trade name tranylcypromine), an antidepressant acting as a monoamine oxidase inhibitor [20 a], of 2,2-dimethylcyclopropane carboxylate from isobutene [20 b], a key step in the commercial production of cilastatin, 3 (eq. (4)), and of esters of chrysanthemic acid 4 (using the methylene bis(diphenyloxazoline) 5) [ 17, 21 ] (eq. (5)). Cilastatin is a dehydropeptidase which acts as an in vivo stabilizer of the car-bapenem antibiotic imipenem with achiral diazoesters. 

The QSAR analysis of the monoamine oxidase (MAO) inhibitors by Kutter and Hansch is one of the earliest successes in the application of Es constante). They... 

Monoamine oxidase From physiology and pathophysiology to the design and clinical application of reversible inhibitors, 23, 65... 

Youdim MB, WeinstockM. Therapeutic applications of selective and non selective inhibitors of monoamine oxidase A and B that do not cause significant tyramine potentiation. Neurotoxicology. 2004 25 243-250. 

In the above described carbonylation reactions the nucleophile that reacts with the species released from the catalytic cycle is water or possibly an alcohol. This can be replaced by a more nucleophilic amine, yielding an amide as the product [66]. With this minor variation a different group of products becomes accessible. A striking application of this reaction is the synthesis of the monoamine oxidase B inhibitor Lazabemide [70, 75]. The first laboratory synthesis could be shortened from 8 steps to just one catalytic reaction with a TON of 3000 (Scheme 5.41). The only drawback to the greenness of this reaction is that the metal is removed via an extraction with aqueous NaCN. 

Acridines are also known therapeutic agent as inhibitors of monoamine oxidases, NADH-dehydrogenases etc. [151, 152]. Numerous studies regarding these applications have been described [153, 154]. Therefore, the synthesis of new tetracyclic acridine compounds has increased rapidly in the last few years. 

Hence, it is not surprising that this type of carbonylation reaction has found application in industry. The pilot plant production of Lazabemide, a monoamine oxidase B inhibitor, by Hofmann-La Roche started from simple 2,5-dichloropyridine. The original eight-step laboratory synthesis of Lazabemide was replaced by a one-step protocol (eq. (11)) [56]. The product is isolated in 65 % yield. As only small amounts of catalyst have to be used (TON = 30(X)), traces of palladium in the product could be removed by appropriate work-up. 

A novel series of tacrine-selegiline hybrids for application as inhibitors of cholinesterase (AChE/BuChE) and monoamine oxidase (MAO-A/B) have also been synthesized [181]. 

Figure 5.12 shows a plot of a set of inhibitors of the enzyme monoamine oxidase (MAO) described by steric (E ) and hydrophobic (n) parameters. It can be seen that the seven active compounds mostly cluster in the top left-hand quadrant of the plot. The original data set involved a dummy parameter, D, to indicate substitution by OCH3 or OH at a particular position, and in the application of CSA to this problem, a set of random... 

Stereotaxic application of drugs to feline caudate has established that the stereotyped behaviour produced by amphetamine, apomorphine, dopamine, and 3-methoxytyramine depends upon the presence of free dopamine receptors and dopamine [574], Caudate dopamine is metabolised by a monoamine oxidase isoenzyme [575], and elucidation of its structure and function might allow the use of a specific inhibitor as an adjunct to L-dopa therapy. Nigral melanin apparently utilises only dopa and dopamine in its formation, and the decreased melanin pigmentation in Parkinsonism may well be a consequence of the decreased availability of these substrates [576]. 

Pargyline is a potent irreversible inhibitor of a flavin-linked monoamine oxidase (MAO) and has found clinical application. The latter catalyzes the inactivation of biologically important catecholamines. It forms a covalent bond with the enzyme via the flavin cofactor and the mode of action is believed to be as shown in Scheme 7.1. 

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