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COMT inhibitors are a class of drugs that inhibit the action of the enzyme catechol-O-methyl transferase (COMT). COMT is a Phase II biotransformation enzyme that metabolizes molecules that contain a catechol group, including the catecholamine group of neurotransmitters (dopamine, epinephrine, and norepinephrine). COMT inhibitors are used in the treatment of Parkinson's disease in combination with levodopa (L-DOPA) and a DOPA decarboxylase inhibitor (DDCI). The addition of a COMT inhibitor to the DDCI treatment can help to further stabilize levels of levodopa in the periphery and increase the amount that reaches the brain, where it can be converted to dopamine.

Mechanism of Action
COMT inhibitors are used clinically to prevent COMT from metabolizing levodopa into dopamine. COMT was initially characterized as an enzyme that transfers a methyl group from s-adenosyl-L-methionine to a catechol substrate in the presence of magnesium and generates an O-methylated catechol and s-adenosyl-L-homocysteine as products. . The three approved COMT pharmaceuticals, entacapone, tolcapone, and opicapone, all use a nitrocatechol group to specifically target the COMT enzyme, not the methyl donor. All three are considered poor substrates for COMT, and are characterized as fully reversible, tight-binding inhibitors.

First Generation Inhibitors
COMT was first isolated in 1957 from rat liver, and in 1958 Julius Axelrod, a future Nobel Laureate, first described its function of transferring a methyl group to epinephrine. Discovery of COMT inhibitors followed shortly behind the discovery of the enzyme itself. Due to its roll in neurotransmitter degradation, COMT immediately became a target of interest for pharmaceutical inhibition. A number of structurally simple COMT competitive inhibitors were quickly identified, with almost all of them falling into one of two classes: catechols or pyrogallols. These compounds inhibited COMT, but inhibition was weak and non-specific. Some of these compounds were tested in Parkinson's disease patients, but they lacked efficacy in the trials. The first-generation inhibitors were found to have very poor pharmacokinetic properties, specifically short half-lives and rapid clearance. They also inhibited other enzymes involved in the metabolism of catecholamines and caused toxicity at higher doses in animal studies. First generation COMT inhibitors continued to be used as tool compounds for researchers, but could not be used clinically due to the toxicity concerns and lack of efficacy.

Despite the clinical failure of first generation COMT inhibitors, the 1970s discovery of the role of COMT in levodopa (L-DOPA) metabolism increased interest in improved COMT inhibitors that could be used clinically. Levodopa is a dopamine precursor that has been used as a treatment for Parkinson's disease since the 1960s. It was soon discovered that Levodopa was heavily metabolized and less than 1% of the dose was able to reach the brain to restore the dopamine depletion that characterizes Parkinson's disease. The majority of this metabolism was conversion of Levodopa to dopamine, which cannot penetrate the blood-brain barrier, by dopa decarboxylase. The use of peripheral DOPA decarboxylase inhibitors (DDCI) such as carbidopa was quickly introduced to inhibit dopamine production from Levodopa in the periphery. In patients treated with Levodopa and a DDCI, scientists discovered the activity of COMT had greatly increased to make up for the lack of DOPA decarboxylase. When Levodopa was administered as a monotherapy, COMT had metabolized about 10% of the Levodopa, converting it to 3-O-methyldopa (3-OMD). With the Levodopa/DDCI combination therapy, the levels of 3-OMD produced by COMT are many times higher. Worse yet, the increased levels of 3-OMD then compete with Levodopa for the same transporter in the intestine, preventing initial absorption of levodopa, and at the blood-brain barrier, preventing levodopa from entering the brain. It was hypothesized that the addition of a selective COMT inhibitor to the combination therapy could help further stabilize levels of Levodopa in the bloodstream and improve delivery to the brain.

Second Generation Inhibitors
It was not until the mid-1980s that more potent and specific COMT inhibitors were discovered. Scientists at two pharmaceutical companies, Hoffman-la Roche and Orion, independently discovered a key chemcial substitution that allowed for the creation of more potent inhibitors. The substitution of a strong electron-withdrawing group at the ortho-position to one of the catechol's two hydroxyl groups produced greatly improved COMT inhibitors. Almost all of the resulting group of second generation COMT inhibitors incorporated a nitro group (-NO2), creating a nitrocatechol structure. Through structure-activity relationship studies, these nitrocatechol compounds became up to 1000 times more potent than first generation compounds. The new compounds were also highly selective for COMT, with none of the off-target inhibition of other catecholamine metabolic enzymes seen previously. . The pharmacokinetic properties of these compounds are still far from ideal, with a short half-life in humans of 2-3 hours. Entacapone, tolcapone, and nitecapone were all tested in clinical trials, but only entacapone and tolcapone have been approved for clinical use to treat Parkinson's disease. Development of nitecapone was halted due to a lack of efficacy in Phase II clinical trials. Tolcapone was approved by the FDA in 1998 as an oral tablet to be used in conjunction with with levodopa/carbidopa therapy to treat Parkinson's disease. An oral tablet of Entacapone was approved by the FDA in 1999 for the same indication. Entacapone has been much more widely used in patients, mainly due to liver toxicity associated with tolcapone.

Newer COMT Inhibitors
Since the approval of entacapone and tolcapone in the late 1990s, researchers have continued to try and develop improved COMT inhibitors. Most of these inhibitors still use the nitrocatechol group to maintain specificity for COMT but aim to improve in vivo function through additional strategies, including novel sidechain substitutions to improve bioavailability, a prodrug strategy to improve water solubility, and a bifunctional inhibition strategy that targets both COMT and the methyl donor s-adenosyl methionine. Only two of these compounds have been tested in humans. Nebicapone was found to have a similar profile to tolcapone, and its development was stopped due to safety concerns. Opicapone has demonstrated a uniquely sustained inhibition of COMT that allows it to be given as a single oral dose. It was approved for use in combination with levodopa to treat Parkinson's disease by the European Commission in 2016.

Clinical Use
To-date, entacapone, tolcapone, and opicapone have been approved for use as an adjunct Parkinson's disease treatment, supplementing treatment with levodopa and a DOPA decarboxylase inhibitor. However, due to the role of COMT in catecholamine metabolism, the use of COMT inhibitors has been investigated in other movement, depressive, and dopamine-associated indications such as :
 * restless leg syndrome (RLS)
 * schizophrenia
 * depression
 * bipolar disorder
 * gastrointestinal disturbances
 * attention deficit disorder (ADD)
 * attention deficit hyperactivity disorder (ADHD)

Safety/Adverse Events
Second generation COMT inhibitors are generally well-tolerated. The most common non-dopaminergic adverse events are diarrhea, abdominal pain, headache, and constipation. Severe diarrhea is the most common reason for discontinuation of treatment, and occurs more commonly with the use of tolcapone than entacapone. The most serious potential adverse event associated with the use of COMT inhibitors is liver toxicity. Both entacapone and tolcapone can result in the transient elevation of liver enzymes, but tolcapone has been associated with more severe hepatotoxicity. Three fatal cases of hepatotoxcity were attributed to tolcapone after about one year of clinical use, resulting in a temporary removal from the market and the requirement of liver monitoring in patients upon its reintroduction. It is unclear why tolcapone causes more severe liver toxicity than entacapone, despite the two molecules sharing the same nitrocatechol structure. Most adverse events associated with these inhibitors are due to the increase in levodopa concentrations resulting from COMT inhibition. Levodopa-associated dyskinesia is by far the most common dopamine-associated adverse event, followed by nausea and vomiting. These events can typically be managed by lowering the dose of levodopa once COMT inhibitor treatment has begun.