Catechol-O-methyltransferase inhibitor explained

A catechol-O-methyltransferase inhibitor (COMT inhibitor) is a drug that inhibits the enzyme catechol-O-methyltransferase. This enzyme methylates catecholamines such as dopamine, norepinephrine and epinephrine. It also methylates levodopa. COMT inhibitors are indicated for the treatment of Parkinson's disease in combination with levodopa and an aromatic L-amino acid decarboxylase inhibitor (e.g. carbidopa or benserazide). 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 of levodopa. COMT inhibitors significantly decrease off time in people with Parkinson's disease also taking carbidopa/levodopa.[1]

List of COMT inhibitors

Entacapone and opicapone are peripherally selective inhibitors, unable to cross the blood–brain barrier (BBB), and hence do not inhibit COMT in the brain. Tolcapone also appears to be peripherally selective.[2] However, it has been found to cross the BBB to at least some degree and significantly inhibit COMT in the brain as well.[3] [4] 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 and is thus only rarely prescribed.[5] Patients taking tolcapone must be monitored for hepatic failure. Entacapone and opicapone have not been associated with hepatotoxicity.[6] [7]

Adverse effects

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 disorders.[8] [9] However, while preclinical research was conducted, development was discontinued. Tolcapone, which acts centrally in addition to peripherally, has shown antidepressant-like effects in animal models of depression.[10] However, these antidepressant-like effects may only occur with combination treatment of tolcapone with levodopa and an aromatic L-amino acid decarboxylase inhibitor. In animals, tolcapone by itself does not increase dopamine levels in the striatum, nucleus accumbens, or frontal cortex, but does augment brain L-DOPA levels when combined with levodopa and benserazide.[11] There may be compensatory activation of the monoamine oxidase dopamine-metabolizing pathway with brain COMT inhibition.

See also

References

[12]

Notes and References

  1. Nov 1997. Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Parkinson Study Group. Annals of Neurology. 42. 5. 747–755. 10.1002/ana.410420511. 0364-5134. 9392574. 975995.
  2. Keating GM, Lyseng-Williamson KA . Tolcapone: a review of its use in the management of Parkinson's disease . CNS Drugs . 19 . 2 . 165–184 . 2005 . 15697329 . 10.2165/00023210-200519020-00006 . The efficacy of tolcapone as an adjunct to levodopa in patients with Parkinson's disease has primarily been attributed to its ability to inhibit peripheral it is thought that tolcapone enters the CNS to a minimal extent only.[16] However, results [17] of a study in patients with Parkinson's disease, as well as results of animal studies,[18-21] suggest that tolcapone also has central activity..
  3. Truong DD . Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease . Clin Interv Aging . 4 . 109–13 . 2009 . 19503773 . 2685232 . 10.2147/cia.s3787 . free . Tolcapone is a potent, selective and reversible inhibitor of COMT in the periphery.8 It also exerts COMT inhibition in the brain, but the relevance of this effect to its efficacy in PD is less clear.9 [...] Although tolcapone has been shown to inhibit central COMT, its clinical efficacy seems to be mainly mediated through inhibition of peripheral COMT and depends on concomitant use of exogenous levodopa.17.
  4. Lang. Anthony E.. Connolly. Barbara S.. 2014-04-23. Pharmacological Treatment of Parkinson Disease: A Review. JAMA. en. 311. 16. 1670–1683. 10.1001/jama.2014.3654. 24756517. 0098-7484.
  5. Olanow. C. Warren. Watkins. Paul B.. Sep 2007. Tolcapone: an efficacy and safety review. Clinical Neuropharmacology. 30. 5. 287–294. 10.1097/wnf.0b013e318038d2b6. 0362-5664. 17909307. 19148461.
  6. Scott. Lesley J.. 2016-08-06. Opicapone: A Review in Parkinson's Disease. Drugs. 76. 13. 1293–1300. 10.1007/s40265-016-0623-y. 27498199. 5787752. 0012-6667.
  7. Watkins. P. COMT inhibitors and liver toxicity. Neurology. 2000. 55 . 11 Suppl 4. S51-2. 11147510.
  8. Web site: Research programme: COMT inhibitors (Alternative Names: AVTX-406; CERC 425; CERC-406) . AdisInsight . 28 January 2022 . 10 July 2024.
  9. Web site: Prospectus Supplement No. 45 . 10 July 2024 . May 11, 2018 . CERC-406 and CERC-425: Residual Motoric and Cognitive Impairment. CERC-406 and CERC-425 are preclinical candidates from our proprietary platform of compounds that inhibit catechol-O-methyltransferase, or COMT, within the brain, which we refer to as our COMTi platform. We believe they may have the potential to be developed for the treatment of residual cognitive impairment symptoms such as Parkinson’s disease..
  10. Finberg JP . Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson's disease . J Neural Transm (Vienna) . 126 . 4 . 433–448 . April 2019 . 30386930 . 10.1007/s00702-018-1952-7 . In accord with its ability to enhance CNS catecholamine levels, tolcapone has been shown to possess antidepressant-like behavioral effect in a rat model of chronic stress with production of an anhedonic state produced by self-stimulation of the ventral tegmental area (Moreau et al. 1994), but others, using a standard chronic stress test, found that antidepressant effect appeared only with a combination of COMT-I, l-DOPA and AAADC-I treatment (Mannisto et al. 1995). Tolcapone, and potentially other CNS-active COMTI, could theoretically be useful in treatment of both depressive and motor symptoms of PD, but further developmental work is necessary to establish this joint treatment..
  11. Müller T, Kuhn W, Przuntek H . Therapy with central active catechol-O-methyltransferase (COMT)-inhibitors: is addition of monoamine oxidase (MAO)-inhibitors necessary to slow progress of neurodegenerative disorders? . J Neural Transm Gen Sect . 92 . 2–3 . 187–195 . 1993 . 8369108 . 10.1007/BF01244877 .
  12. Govindasamy. Hunday. Magudeeswaran. Sivanandam. Poomani. Kumaradhas. 2020-12-11. Identification of novel flavonoid inhibitor of Catechol-O-Methyltransferase enzyme by molecular screening, quantum mechanics/molecular mechanics and molecular dynamics simulations. Journal of Biomolecular Structure and Dynamics. 38. 18. 5307–5319. 10.1080/07391102.2019.1699446. 0739-1102. 31779524. 208356889.

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