Monoamine oxidase (MAO) is an enzyme that oxidizes monoamine neurotransmitters and neuromodulators, as well as exogenous bioactive monoamines. It was first characterized by Hare in 1928 and was later called MAO by Zeller in 1938. Following the characterization of this enzyme, it was later discovered that its inhibition could have positive effects on psychiatric disorders such as depression.
Iproniazid, described in the late 1950's and used as a treatment for tuberculosis, was found to have mood-elevating properties. It was later shown to be a suitable MAO inhibitor and was used thereafter as an effective antidepressant. However, the drug had to be withdrawn from the U.S. market in the early 1960's because of the reports of hepatic toxicity and occasional hypertensive crises associated with its use. Still, the success of Iproniazid as an antidepressant stimulated pharmaceutical companies to search for new MAO inhibitors having antidepressant properties without adverse side effects. Since then, a large number of MAO inhibitors have been synthesized and administered.
Until 1972, when it was discovered for the first time that MAO existed in two forms, namely MAO-A and MAO-B, the first generation of MAO inhibitors had no selective inhibitory activity towards MAO-A and/or MAO-B. Examples of these compounds are the drugs phenelzine and tranylcypromine, respectively patented in 1959 (U.S. Pat. No. 3,000,903) and 1961 (U.S.Pat. No. 2,997,422). Apart from inhibiting the activity of both MAO-A and MAO-B, these non-selective irreversible MAO inhibitor antidepressants also exhibit other important drawbacks. Hence, these drugs have been categorized as "dirty" drugs. In other words, they also block other enzymes and most importantly, they can, similarly to Iproniazid, cause severe hepatotoxicity and hypertension resulting from the ingestion of tyramine-rich food and drinks. This is caused by the fact that dietary amines are not broken down after ingestion and thus release circulating catecholamines which may lead to hypertensive crises and sometimes death. Thus, non-selective MAO inhibitors of this type have acquired a bad reputation and although they are very effective antidepressants, they have been avoided by most psychiatrists in favour of the relatively safer tricyclic antidepressants.
In the mid 1960's, a French group headed by Jacques R. Boissier published data on the synthesis of three series of new aliphatic and cycloaliphatic derivatives of hydrazine, propargylamine and cyclopropylamine, suspected to be useful as monoamine oxidase inhibitors (Chimie Therapeutique (1966), 320-326). Boissier et al. suggested that these non-selective total MAO inhibitors might possess therapeutic properties for the treatment of depression or angina pain. In French Patent 1,453,844, N-propynylalkylamines having a linear or branched alkyl group of 7 to 9 carbon atoms on the amino moiety are described.
In a further 1967 publication (Therapie, XXII, 1967, 367-373), Boissier et al. reported the results of tests conducted with these compounds to evaluate their antidepressant activity. Based on the results obtained, Boissier et al. concluded that the aliphatic compounds of the propargylamine series were practically inactive in vivo, regardless of whether the amine was secondary or tertiary, and only moderately active in vitro. From these results, it seemed that a promising future could not be foreseen for aliphatic propargylamines as effective MAO inhibitors. Hence, research involving compounds of this type was completely abandoned after the 1965, '66 and '67 publications by Boissier et al. It turned out that most of the research done later on MAO inhibitors concentrated on aromatic compounds.
In the early 1970's, it gradually became apparent that MAO existed in multiple forms, namely MAO-A and MAO-B. These two types of enzymes have been found to be somewhat different from one another. They exhibit different substrate profiles, they respond differently to selective inhibitors, they are found in different cellular and subcellular locations and they are distributed differently between neuronal and non-neuronal structures. Recently, MAO-A and MAO-B have been shown to arise from different gene loci. MAO-A is located predominantly inside the neurones and is responsible for causing hypertensive crises. It preferentially deaminates and oxidizes 5-hydroxy-tryptamine. As for MAO-B, it is found mostly in glia and it preferentially oxidizes .beta.-phenylethylamine.
The discovery of MAO-A and MAO-B was of major importance since it initiated the research that led to the synthesis of second generation MAO inhibitors. The second generation MAO inhibitors are compounds that irreversibly or reversibly inhibit either the A or the B form of the enzyme. Because both the antidepressant and hypertensive effects are considered to be related to the inhibition of MAO-A, drug companies have concentrated their efforts mainly in the development of MAO-A inhibitors. Clorgyline, Lilly 51641 and PCO were among the first selective MAO inhibitors for MAO-A to be discovered. All these compounds belong to the first category of second generation MAO inhibitors and form irreversible links with the A enzyme.
The reversible specific MAO inhibitors, which form the second category of second generation inhibitors, have recently attracted attention because of their potentially improved clinical properties. Included in this category are harmine, harmaline, cimoxatone, brofaromine, amiflamine and moclobemide.
In recent years, a MAO-A inhibitory prodrug has also been discovered. MDL-72394 can be decarboxylated by aromatic L-amino acid decarboxylase and forms a potent irreversible MAO-A inhibitor, which has been shown to be neuronal selective. The chemical structures of first and second generation aromatic MAO-A and -B inhibitors may be found in Chapter 7 of Neuromethods, Volume 5, Neurotransmitter Enzymes, 1986, Humana Press, the contents of which is hereby incorporated by reference.
Research on MAO-B inhibitors is nowhere near the level of research accomplished so far for MAO-A. In fact, only a few irreversible MAO-B inhibitors such as Deprenyl and Pargyline have so far been discovered. Deprenyl is one of the most important and widely tested MAO-B inhibitors. It has been used as an effective adjuvant to L-DOPA in the treatment of Parkinson's disease. The combination of Deprenyl and L-DOPA seems to reduce the requirement for L-DOPA (presently known to be the best antiparkinsonian agent) in those cases where L-DOPA is being ingested. Recently, it was reported that Deprenyl alone can significantly delay the onset of disability associated with early, otherwise, untreated cases of Parkinson's disease. It has also been claimed that the use of Deprenyl improved the clinical condition of some Alzheimer's patients and reduced depression, attention deficit disorders and potentially other neuropsychiatric disorders. In addition, Deprenyl has been observed to prolong life span and sexual activity in animals and humans. Unlike MAO-A inhibitors, MAO-B inhibitors do not usually cause hypertensive crises except, in some instances, under chronic large-dose applications and therefore have the potential to become very useful neuropsychiatric and geriatric drugs.
Although Deprenyl at higher doses can cause a slight increase in dopamine levels in the brain, the involvement of dopamine in the mechanism of action of Deprenyl has not been well established. The inhibition of MAO-B activity causes a selective accumulation of .beta.-phenylethylamine, a typical MAO-B substrate, which is present endogenously, including in the central nervous system. .beta.-Phenylethylamine, which possesses stimulant properties, can amplify dopaminergic function and modulate dopaminergic neurotransmission and is therefore related to the chemotherapy of MAO-B inhibitors.
It was also found that since Deprenyl is a structural analog of amphetamine, it is catabolized to produce small amounts of amphetamine. This has caused some concern because it was hypothesized that Deprenyl might, in some instances, be a drug subject to substance abuse. Hence, different MAO-B inhibitors not possessing amphetamine-like properties are required. Recently, the reversible MAO-B inhibitors MD 780236 and RO-16-6491 as well as the irreversible inhibitor MDL-72145 were discovered but other alternatives are still being sought. Recent studies on currently available MAO-A and MAO-B inhibitors are summarized in Youdim et al., (1991) Biochemical Pharmacology, Vol. 41, No. 2, pp. 133-162, which is hereby incorporated by reference.
In 1989, the results of a systematic investigation on the deamination by MAO-A and -B of amines having aliphatic chains of various lengths were published (J. Pharm. Pharmacol. 1989, 41:205-208). It was found that these amines were readily oxidized by MAO-B with very high affinity. The deamination of these aliphatic amines by MAO-B was found to be even more sensitive to Deprenyl than that of .beta.-phenylethylamine, which is known to be a typical MAO-B substrate. Unfortunately, although these compounds were found to be good substrates for MAO-B, they did not exhibit any inhibitory activity towards this enzyme.
In summary, active research on MAO inhibitors has been carried out since as early as 1950 and hundreds of potentially useful MAO inhibitors have been synthesized. There was an important change in research focus in the early 1970's when the existence of two different forms of MAO enzymes was discovered. It seems that substantial progress has been made in MAO-A inhibition but much more work remains to be done to find suitable MAO-B inhibitors. Since the inhibition of MAO-B appears to alleviate the symptoms of aging associated diseases such as Parkinson's disease and Alzheimer's disease, suitable MAO-B inhibitors would be highly desirable, especially in view of the limited and relatively inefficient treatments available for these diseases.