What Are Monoamine Oxidase Inhibitors?

Monoamine oxidase (MAO) is a naturally occurring enzyme in the human body that catalyzes the oxidative deamination reaction of monoamines. There are two types of monoamine oxidase in the human body: monoamine oxidase A and monoamine oxidase B. Monoamine oxidase A is mainly distributed in catecholaminergic neurons; monoamine oxidase B is mainly distributed in serotoninergic neurons, histaminergic neurons and glial cells, both of which can make monoamine neurotransmitters Inactivated. Monoamine oxidase inhibitors can reduce or eliminate diseases caused by monoamine oxidase reduction or high monoamine oxidase activity caused by various reasons by inhibiting the oxidation activity of monoamine oxidase on monoamine substances.

Monoamine oxidase (MAO) is a naturally occurring enzyme in the human body that catalyzes the oxidative deamination reaction of monoamines. There are two types of monoamine oxidase in the human body: monoamine oxidase A and monoamine oxidase B. Monoamine oxidase A is mainly distributed in catecholaminergic neurons; monoamine oxidase B is mainly distributed in serotoninergic neurons, histaminergic neurons and glial cells, both of which can make monoamine neurotransmitters Inactivated. Monoamine oxidase inhibitors can reduce or eliminate diseases caused by monoamine oxidase reduction or high monoamine oxidase activity caused by various reasons by inhibiting the oxidation activity of monoamine oxidase on monoamine substances.

Monoamine oxidase inhibitors (MAO inhibitor drugs, MAOID) refer to a class of drugs that can treat various neurological diseases related to MAO. They can be divided into non-selective MAOID, MAO-A inhibitory drugs, and MAO-B inhibitory drugs. These three types of drugs can be divided into reversible and irreversible inhibitory drugs.

Chinese name

Monoamine oxidase inhibitor

Foreign name

monoamine oxidase, MAO

Main

Treatment of various neurological diseases related to MAO

Function

Antidepressant, Parkinson's disease, Alzheimer's disease

By

Inhibition of monoamine oxidase

Effect

Produces antidepressant effects and has anti-Parkinson's

1 Non-selective MAOID

This class of drugs mainly includes phenpromazine, phenethylhydrazine, isocarboxazid, and tranylcypromine. Among them, phenpromazine was the first antidepressant drug. It was tested in patients with depression in 1957 and was successful . These drugs were once widely used clinically for antidepressants. Their main effect is to increase the levels of NA and 5-HT in the brain and reduce the levels of their metabolites. At the same time, the metabolism of tyramine in the body is suppressed and absorbed. The increase promotes the release of NA, causing symptoms such as increased blood pressure, tachycardia, headache, and vomiting. This phenomenon is called the "cheese-like effect". Soon, these drugs were eliminated because they could interact with some foods and drugs, causing severe adverse reactions such as hypertension crisis and acute yellow liver atrophy.

2 MAO-A inhibitors

MAO-A inhibitory drugs refer to a class of drugs that can selectively inhibit MAO-A, which is mainly used to treat depression. Its mechanism of action is that it can reversibly and selectively inhibit MAO-A, preventing 5-HT and NE degrades and increases the concentration of 5-HT and NE in the synaptic cleft in the brain, acting as an antidepressant.

2.1 The oxazolidinone MAO-A inhibitor drug Toloxadone is an antidepressant marketed in France in 1985. It has a strong and reversible inhibitory effect on MAO-A. According to the structure of toloxadone, the modified compound has a stronger inhibitory effect on MAO-A than toloxadone (effective concentrations are all in nmol / L grade), of which (R)-(5-methoxymethyl -3-1 H-pyrrole-1-yl) -2-azolidinone inhibits MAO-A by more than 78 times and selectivity is 6 times that of toloxadone. It is worth noting that after the MAO interacted with the drug was immersed in a 0.1 mol / L phosphate buffer for 24 hours, its activity recovered to more than 90%, which indicates that the effects of these drugs are reversible.

2.2 Inhibitors of quinoxaline MAO-A In recent years, there have been many reports on the synthesis of quinazoline, but research on its use as MAOID is rare. Its derivatives have a good selective inhibitory effect on MAO-A, and doses up to 250 mg / kg have no toxic effect on mice, which means that these compounds have good drug development potential.

2.3 Other classes of MAO-A inhibitors, chlorbemide, a new generation of MAO-A inhibitors that were marketed in the United Kingdom in 1990. They are reversible inhibitors of MAOA and are used to treat depression. , Functional, reactive, and symptomatic depression have curative effects, can be used by young and old, especially suitable for elderly patients. This product has less side effects and is well tolerated. It is not necessary to fast foods containing dairy products during medication. Clojilin can selectively inhibit MAO-A, make 5-HT significantly increase in the nerve endings, and is used to treat depression.

3.MAO-B inhibitory drugs

3.1 MAO-B inhibitors containing phenethylamine or benzylamine

3.1.1 Selegiline is the first generation of irreversible MAO-B selective inhibitory drug. It can be used as a single drug to treat early Parkinson's disease and delay the progression of the disease. If combined with L-DOPA, it can significantly reduce L-DOPA. The resulting "on-off" phenomenon and dyskinesia can effectively alleviate tremor, rigidity and bradykinesia in patients with advanced Parkinson's disease. Selegiline has poor selectivity and large adverse reactions, which can produce nausea, hallucinations, and hypertension crisis. In addition, selegiline combined with L-dopa can reduce the dose of L-dopa, at the same time, it can improve symptoms and delay the progress of the disease. It has a good effect on the treatment of early Parkinson's disease. The second revolution. However, selegiline has many side effects. For example, it has the disadvantages of poor selectivity and large adverse reactions. It can increase the incidence of hypertension and heart disease. It can be metabolized into amphetamine derivatives in the body. Many experts have called for limiting the use of selegiline in Parkinson's disease.

3.1.2 Rasagiline is a second-generation irreversible MAO-B selective inhibitor. Compared with selegiline, it has many advantages. For example, its potency is 5-10 times that of selegiline. It is dose-dependent, has less adverse reactions, and will not be metabolized to amphetamine derivatives. Compared to selegiline, which can only be used in early Parkinson's disease, rasagiline has both early and intermediate stages of Parkinson's disease. Very good effect. A double-blind, delayed-dose trial of rasagiline called ADAGIO showed that 1 mg / d of rasagiline reduced the average daily off-time and improved L-dopa treatment Symptoms of Parkinson's disease in fluctuating patients. Rasagiline is currently the main MAO-B inhibitor in the treatment of Parkinson's disease. A number of studies have shown that Rasagiline has neuroprotective and disease modifying effects, and its mechanism may be through intervention in mitochondrial death. Signal pathways matter. It can increase the expression of anti-apoptotic Bcl-2 protein family and neurotrophic factors. Neurotrophic factors, especially glial cell-derived neurotrophic factors and brain-derived neurotrophic factors, have the effect of protecting and promoting the growth of nerve cells. However, due to its insufficient selectivity for two MAOs, and its irreversible inhibition of enzyme activity is still not an ideal drug.

3.1.3 Safinamide The third-generation monoamine oxidase B inhibitor Safinamide has entered the Phase III clinical trial. It is a new, highly effective, reversible, and highly specific MAO-B inhibitor. Its inhibitory intensity on MAO-B is 5000 times that of MAO-A, while selegiline is 127 times and rasagiline is 103 times. Its inhibitory effect on MAO-B is reversible, and physiological functions can be fully restored 8 hours after stopping the drug. Multiple randomized, double-blind, controlled trials of safinamide show that taking 50-100 mg safinamide daily can effectively control the symptoms of Parkinson's disease, and the patient's unified Parkinson's disease rating scale score has significantly increased compared to the placebo group. In addition, some studies have shown that the mechanism of safenamide to relieve the symptoms of Parkinson's disease is not only inhibition of MAO-B, but also many additional mechanisms of action, such as inhibition of glutamate release and inhibition of sodium ion channel opening, etc. Other mechanisms have not yet been clarified, and further research is needed in the future.

3.2 Nitrogen-containing 5-membered ring MAO-B inhibitors

3.2.1 Pyrrole MAO-B inhibitors According to the literature, in the structure-activity relationship of pyrrole MAO-B inhibitors, pyrrole derivatives and their related amine alcohol compounds have the activity of inhibiting MAO-B.

3.2.2 Pyrazole MAO-B inhibitory drugs According to literature reports, compounds containing 3,5-diphenylpyrazole structure have a strong and reversible inhibitory effect on MAO-B. When pyrazole N1 position H is benzoyl or ammonia Methionyl substitution decreases the selectivity. The imidazole 2-position substitute had higher activity (IC50 was 3.63 mol / L), and the compound had good selectivity (SI: 31.05).

3.2.3 Thiazole MAO-B inhibitors According to the literature, 2-hydrazino-4-m-methoxyphenylthiazole derivatives have a good irreversible inhibitory effect on MAO. It has a good inhibitory effect on MAO-B.

3.2.4 Indole MAO-B inhibitory drug Indole is a benzopyrrole coplanar compound, which exists widely in nature. Natural products containing indole structure have become the largest number of alkaloids and have important pharmacological effects. For example, indole oxide isatin is a reversible MAOID, which has a strong selective inhibitory effect on MAO-B. Isatin's 5-substituted or 6-substituted styryl, benzyloxy or phenoxy derivatives are selective and reversible inhibitors.

3.3 Flavonoids MAO-B inhibitory drugs Flavones refer to a large class of phenolic compounds based on the benzophenone ring. Naturally occurring flavonoids can be divided into flavonoids, flavonols, and chalcone, among which flavonoids generally refer to two benzene rings (A-ring and B-ring) with phenolic hydroxyl groups connected by a central three carbon atom to each other. Into a series of compounds, the basic mother core is 2-phenylchromogenone. There are more than 8,000 known flavonoids, which can not only reduce the formation of free radicals, but also scavenge free radicals in the body to regulate the biological activities of various enzymes such as MAO. It has been reported in the literature that 3-phenylflavones and 3-phenylthioflavones have a strong inhibitory effect on MAO-B.

3.4 Coumarins MAO-B inhibitory drug Coumarin is chemically named 2 H-1-benzopyran-2-one, which can be divided into simple coumarin and furan according to the different substituents on the coumarin ring. Coumarin, pyrancoumarin and other types of coumarin. This class of compounds exists widely in nature and is distributed in many higher plants such as Rutaceae, Umbelliferae, Solanaceae and Leguminosae, and has anti-MAO, anti-acetylcholinesterase, anti-tumor, anti-oxidant and anti-inflammatory effects. ^[1]

Currently MAO inhibitory drugs have an irreplaceable role in the treatment of depression, anti-Parkinson's disease and Alzheimer's disease. For this reason, MAOIDs with various new structures are continuously designed and synthesized in order to find MAOIDs suitable for clinical applications, with small side effects, reversible and selective, and better used for the treatment of various neurodegenerative diseases.