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Catechol-O-methyltransferase inhibitor

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Metabolism of levodopa by catechol-O-methyltransferase (COMT) and aromatic L-amino acid decarboxylase (AADC). COMT inhibitors prevent the conversion of levodopa to 3-O-methyldopa.

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

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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.[2][3][4] However, the clinical relevance of its COMT inhibition in the brain in Parkinson's disease is uncertain.[3] 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.[3]

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

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

Research

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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.[8] 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.[10] 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.[11]

See also

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References

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  1. ^ "Entacapone improves motor fluctuations in levodopa-treated Parkinson's disease patients. Parkinson Study Group". Annals of Neurology. 42 (5): 747–755. Nov 1997. doi:10.1002/ana.410420511. ISSN 0364-5134. PMID 9392574. S2CID 975995.
  2. ^ a b Keating GM, Lyseng-Williamson KA (2005). "Tolcapone: a review of its use in the management of Parkinson's disease". CNS Drugs. 19 (2): 165–184. doi:10.2165/00023210-200519020-00006. PMID 15697329. 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. ^ a b c Truong DD (2009). "Tolcapone: review of its pharmacology and use as adjunctive therapy in patients with Parkinson's disease". Clin Interv Aging. 4: 109–13. doi:10.2147/cia.s3787. PMC 2685232. PMID 19503773. 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. 311 (16): 1670–1683. doi:10.1001/jama.2014.3654. ISSN 0098-7484. PMID 24756517.
  5. ^ Olanow, C. Warren; Watkins, Paul B. (Sep 2007). "Tolcapone: an efficacy and safety review". Clinical Neuropharmacology. 30 (5): 287–294. doi:10.1097/wnf.0b013e318038d2b6. ISSN 0362-5664. PMID 17909307. S2CID 19148461.
  6. ^ Scott, Lesley J. (2016-08-06). "Opicapone: A Review in Parkinson's Disease". Drugs. 76 (13): 1293–1300. doi:10.1007/s40265-016-0623-y. ISSN 0012-6667. PMID 27498199. S2CID 5787752.
  7. ^ Watkins, P (2000). "COMT inhibitors and liver toxicity". Neurology. 55 (11 Suppl 4): S51-2. PMID 11147510.
  8. ^ a b "Research programme: COMT inhibitors (Alternative Names: AVTX-406; CERC 425; CERC-406)". AdisInsight. 28 January 2022. Retrieved 10 July 2024.
  9. ^ "Prospectus Supplement No. 45" (PDF). May 11, 2018. Retrieved 10 July 2024. 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. ^ a b Finberg JP (April 2019). "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. doi:10.1007/s00702-018-1952-7. PMID 30386930. 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. ^ a b Müller T, Kuhn W, Przuntek H (1993). "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. doi:10.1007/BF01244877. PMID 8369108.

[1]

  1. ^ 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. doi:10.1080/07391102.2019.1699446. ISSN 0739-1102. PMID 31779524. S2CID 208356889.
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