A catechol-''O''-methyltransferase inhibitor (COMT inhibitor) is a drug that inhibits the enzyme catechol-''O''-methyltransferase. This enzyme methylates

catecholamines A catecholamine (; abbreviated CA), most typically a 3,4-dihydroxyphenethylamine, is a monoamine neurotransmitter, an organic compound that has a catechol (benzene with two hydroxyl side groups next to each other) and a side-chain amine. ...

such as

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...

and

epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...

. It also methylates

levodopa Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease (PD) and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. ...

. COMT inhibitors are indicated for the treatment of

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

combination In mathematics, a combination is a selection of items from a set that has distinct members, such that the order of selection does not matter (unlike permutations). For example, given three fruits, say an apple, an orange and a pear, there are ...

with levodopa and an

aromatic L-amino acid decarboxylase inhibitor An aromatic L-amino acid decarboxylase inhibitor (synonyms: DOPA decarboxylase inhibitor, extracerebral decarboxylase inhibitor, DDCI and AAADI) is a medication of type enzyme inhibitor which inhibits the synthesis of dopamine by the enzyme a ...

(e.g.

carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...

benserazide Benserazide is a peripherally acting aromatic L-amino acid decarboxylase or DOPA decarboxylase inhibitor, which is unable to cross the blood–brain barrier. It is on the World Health Organization's List of Essential Medicines. Medical use ...

). The therapeutic benefit of using a COMT inhibitor is based on its ability to prevent the methylation of levodopa to 3-''O''-methyldopa, thus increasing the

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.

List of COMT inhibitors

* Marketed **

Entacapone Entacapone, sold under the brand name Comtan among others, is a medication commonly used in combination with other medications for the treatment of Parkinson's disease. Entacapone together with levodopa and carbidopa allows levodopa to have a lo ...

(Comtan, Comtess, Stalevo) **

Opicapone Opicapone, sold under the brand name Ongentys, is a medication which is administered together with levodopa in people with Parkinson's disease. Opicapone is a Catechol-O-methyltransferase inhibitor, catechol-O-methyltransferase (COMT) inhibito ...

(Ongentys) **

Tolcapone Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinson's disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-''O''-methyltransferase (COMT). It has demonstra ...

(Tasmar) * Not marketed ** Nebicapone (BIA 3-202) ** Neluxicapone **

Nitecapone Nitecapone (INN; OR-462) is a drug which acts as a selective inhibitor of the enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called sub ...

(OR-462) Entacapone and opicapone are peripherally selective inhibitors, unable to cross the

blood–brain barrier The blood–brain barrier (BBB) is a highly selective semipermeable membrane, semipermeable border of endothelium, endothelial cells that regulates the transfer of solutes and chemicals between the circulatory system and the central nervous system ...

(BBB), and hence do not inhibit COMT in the brain. Tolcapone also appears to be peripherally selective. However, it has been found to cross the BBB to at least some degree and significantly inhibit COMT in the brain as well. However, the clinical relevance of its COMT inhibition in the brain in Parkinson's disease is uncertain. Instead, the drug seems to exert most of its clinical efficacy in this condition through inhibition of peripheral COMT and is dependent on concomitant use of levodopa. Tolcapone has been associated with at least three fatal cases of

acute liver failure Acute liver failure is the appearance of severe complications rapidly after the first signs (such as jaundice) of liver disease, and indicates that the liver has sustained severe damage (loss of function of 80–90% of liver cells). The complicati ...

and is thus only rarely prescribed. Patients taking tolcapone must be monitored for hepatic failure. Entacapone and opicapone have not been associated with hepatotoxicity.

Adverse effects

* nausea * orthostatic hypotension * vivid dreams * confusion * hallucinations * hepatotoxicity (only tolcapone) * diarrhea * drowsiness * urine discoloration * dyskinesia

Research

Centrally acting COMT inhibitors like CERC-406 and CERC-425 that inhibit COMT in the brain in addition to the periphery were under investigation for potential treatment of residual cognitive impairment symptoms in Parkinson's disease and of

depressive disorder A mood disorder, also known as an affective disorder, is any of a group of conditions of mental disorder, mental and Abnormal behavior, behavioral Disorder (medicine), disorder where the main underlying characteristic is a disturbance in the per ...

s. However, while

preclinical research In drug development, preclinical development (also termed preclinical studies or nonclinical studies) is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and dr ...

was conducted, development was discontinued.

, which acts centrally in addition to peripherally, has shown

antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...

-like effects in

animal model An animal model (short for animal disease model) is a living, non-human, often genetic-engineered animal used during the research and investigation of human disease, for the purpose of better understanding the disease process without the risk of ha ...

s of depression. However, these antidepressant-like effects may only occur with

treatment of tolcapone with

and an aromatic L-amino acid decarboxylase inhibitor. In animals, tolcapone by itself does not increase dopamine levels in the

striatum The striatum (: striata) or corpus striatum is a cluster of interconnected nuclei that make up the largest structure of the subcortical basal ganglia. The striatum is a critical component of the motor and reward systems; receives glutamat ...

nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for ' nucleus adjacent to the septum') is a region in the basal forebrain rostral to the preoptic area of the hypo ...

, or

frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betw ...

, but does augment brain L-DOPA levels when combined with levodopa and

. There may be compensatory activation of the

monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...

dopamine-metabolizing pathway with brain COMT inhibition.

References

{{Antiparkinson Catechol-O-methyltransferase inhibitors Peripherally selective drugs

List of COMT inhibitors

Adverse effects

Research

See also

References