Skip to main content

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility

Abstract

Rationale

Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity.

Objectives

To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates.

Methods

We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone.

Results

We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration.

Conclusions

These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3

References

  1. Acquas E, Carboni E, de Ree RH, Da Prada M, Di Chiara G (1992) Extracellular concentrations of dopamine and metabolites in the rat caudate after oral administration of a novel catechol-O-methyltransferase inhibitor Ro 40-7592. J Neurochem 59:326–330

    CAS  PubMed  Article  Google Scholar 

  2. Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, Alce G, Iudicello JE, Akbar N, Egan MF, Goldberg TE, Weinberger DR (2007) Tolcapone improves cognition and cortical information processing in normal human subjects. Neuropsychopharmacology 32:1011–1020

    CAS  PubMed  Article  Google Scholar 

  3. Apud JA, Weinberger DR (2007) Treatment of cognitive deficits associated with schizophrenia: potential role of catechol-O-methyltransferase inhibitors. CNS Drugs 21:535–557

    CAS  PubMed  Article  Google Scholar 

  4. Axelrod J, Tomchick R (1958) Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 233:702–705

    CAS  PubMed  Google Scholar 

  5. Beeldman E, Raaphorst J, Klein Twennaar M, Govaarts R, Pijnenburg YAL, de Haan RJ, de Visser M, Schmand BA (2018) The cognitive profile of behavioural variant FTD and its similarities with ALS: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 89:995–1002

    PubMed  Article  Google Scholar 

  6. Birrell JM, Brown VJ (2000) Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20:4320–4324

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  7. Buchler I, Akuma D, Au VQ, Carr G, de Leon P, DePasquale M, Ernst G, Huang Y, Kimos M, Kolobova A, Poslusney MS, Wei H, Swinnen D, Montel F, Moureau F, Jigorel E, Schulze MS, Wood M, Barrow JC (2018) Optimization of 8-hydroxyquinolines as inhibitors of catechol O-methyltransferase. J Med Chem. 61:9647–9665

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. Cameron IGM, Wallace DL, Al-Zughoul A, Kayser AS, D'Esposito M (2018) Effects of tolcapone and bromocriptine on cognitive stability and flexibility. Psychopharmacology (Berl) 235:1295–1305

    CAS  Article  Google Scholar 

  9. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807–821

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  10. Dias R, Robbins TW, Roberts AC (1996) Primate analogue of the Wisconsin Card Sorting Test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav Neurosci 110:872–886

    CAS  PubMed  Article  Google Scholar 

  11. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci U S A 98:6917–6922

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. Ernst G, Akuma D, Au V, Buchler IP, Byers S, Carr GV, Defays S, de Leon P, Demaude T, DePasquale M, Durieu V, Huang Y, Jigorel E, Kimos M, Kolobova A, Montel F, Moureau F, Poslusney M, Swinnen D, Vandergeten M-C, Van houtvin N, Wei H, White N, Wood M, Barrow JC (2019) Synthesis and evaluation of bicyclic hydroxypyridones as inhibitors of Catechol-O-Methyltransferase. ACS Med. Chem. Lett. 10(11):1573–1578

  13. Gallagher CL, Bell B, Palotti M, Oh J, Christian BT, Okonkwo O, Sojkova J, Buyan-Dent L, Nickles RJ, Harding SJ, Stone CK, Johnson SC, Holden JE (2015) Anterior cingulate dopamine turnover and behavior change in Parkinson’s disease. Brain Imaging Behav 9:821–827

    PubMed  PubMed Central  Article  Google Scholar 

  14. Gasparini M, Fabrizio E, Bonifati V, Meco G (1997) Cognitive improvement during Tolcapone treatment in Parkinson’s disease. J Neural Transm (Vienna) 104:887–894

    CAS  Article  Google Scholar 

  15. Grant JE, Odlaug BL, Chamberlain SR, Hampshire A, Schreiber LR, Kim SW (2013) A proof of concept study of tolcapone for pathological gambling: relationships with COMT genotype and brain activation. Eur Neuropsychopharmacol 23:1587–1596

    CAS  PubMed  Article  Google Scholar 

  16. Gratwicke J, Jahanshahi M, Foltynie T (2015) Parkinson’s disease dementia: a neural networks perspective. Brain 138:1454–1476

    PubMed  PubMed Central  Article  Google Scholar 

  17. Haasio K (2010) Toxicology and safety of COMT inhibitors. Int Rev Neurobiol 95:163–189

    CAS  PubMed  Article  Google Scholar 

  18. Hsu WY, Lane HY, Lin CH (2018) Medications used for cognitive enhancement in patients with schizophrenia, bipolar disorder, Alzheimer’s disease, and Parkinson’s disease. Front Psychiatry 9:91

    PubMed  PubMed Central  Article  Google Scholar 

  19. Jain R, Katic A (2016) Current and investigational medication delivery systems for treating attention-deficit/hyperactivity disorder. Prim Care Companion CNS Disord 18

  20. Kaenmaki M, Tammimaki A, Myohanen T, Pakarinen K, Amberg C, Karayiorgou M, Gogos JA, Mannisto PT (2010) Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice. J Neurochem 114:1745–1755

    CAS  PubMed  Article  Google Scholar 

  21. Keefe RS (2014) Cognition and motivation as treatment targets in schizophrenia. JAMA Psychiatry 71:987–988

    PubMed  Article  Google Scholar 

  22. Laatikainen LM, Sharp T, Harrison PJ, Tunbridge EM (2013) Sexually dimorphic effects of catechol-O-methyltransferase (COMT) inhibition on dopamine metabolism in multiple brain regions. PLoS One 8:e61839

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. Lane CA, Hardy J, Schott JM (2018) Alzheimer’s disease. Eur J Neurol 25:59–70

    CAS  PubMed  Article  Google Scholar 

  24. Lapish CC, Ahn S, Evangelista LM, So K, Seamans JK, Phillips AG (2009) Tolcapone enhances food-evoked dopamine efflux and executive memory processes mediated by the rat prefrontal cortex. Psychopharmacology (Berl) 202:521–530

    CAS  Article  Google Scholar 

  25. Lee LO, Prescott CA (2014) Association of the catechol-O-methyltransferase val158met polymorphism and anxiety-related traits: a meta-analysis. Psychiatr Genet 24:52–69

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. Lewis DA, Melchitzky DS, Sesack SR, Whitehead RE, Auh S, Sampson A (2001) Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J Comp Neurol 432:119–136

    CAS  PubMed  Article  Google Scholar 

  27. Limousin P, Pollak P, Gervason-Tournier CL, Hommel M, Perret JE (1993) Ro 40-7592, a COMT inhibitor, plus levodopa in Parkinson’s disease. Lancet 341:1605

    CAS  PubMed  Article  Google Scholar 

  28. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210

    CAS  PubMed  Article  Google Scholar 

  29. Mahat MY, Fakrudeen Ali Ahamed N, Chandrasekaran S, Rajagopal S, Narayanan S, Surendran N (2012) An improved method of transcutaneous cisterna magna puncture for cerebrospinal fluid sampling in rats. J Neurosci Methods 211:272–279

    PubMed  Article  Google Scholar 

  30. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D (2002) A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 159:652–654

    PubMed  Article  Google Scholar 

  31. Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, Kleinman JE, Weinberger DR (2003) Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116:127–137

    CAS  PubMed  Article  Google Scholar 

  32. McCane AM, DeLory MJ, Timm MM, Janetsian-Fritz SS, Lapish CC, Czachowski CL (2018) Differential COMT expression and behavioral effects of COMT inhibition in male and female Wistar and alcohol preferring rats. Alcohol 67:15–22

    CAS  PubMed  Article  Google Scholar 

  33. Meiser J, Weindl D, Hiller K (2013) Complexity of dopamine metabolism. Cell Commun Signal 11:34

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  34. Miskowiak KW, Kjaerstad HL, Stottrup MM, Svendsen AM, Demant KM, Hoeffding LK, Werge TM, Burdick KE, Domschke K, Carvalho AF, Vieta E, Vinberg M, Kessing LV, Siebner HR, Macoveanu J (2017) The catechol-O-methyltransferase (COMT) Val158Met genotype modulates working memory-related dorsolateral prefrontal response and performance in bipolar disorder. Bipolar Disord 19:214–224

    CAS  PubMed  Article  Google Scholar 

  35. Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT (2002) Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 22:389–395

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. Muller T, Investigators TS (2014) Tolcapone addition improves Parkinson’s disease associated nonmotor symptoms. Ther Adv Neurol Disord 7:77–82

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. Muslimovic D, Post B, Speelman JD, Schmand B (2005) Cognitive profile of patients with newly diagnosed Parkinson disease. Neurology 65:1239–1245

    PubMed  Article  Google Scholar 

  38. Nieoullon A (2002) Dopamine and the regulation of cognition and attention. Prog Neurobiol 67:53–83

    CAS  PubMed  Article  Google Scholar 

  39. Nirogi R, Kandikere V, Mudigonda K, Bhyrapuneni G, Muddana N, Saralaya R, Benade V (2009) A simple and rapid method to collect the cerebrospinal fluid of rats and its application for the assessment of drug penetration into the central nervous system. J Neurosci Methods 178:116–119

    CAS  PubMed  Article  Google Scholar 

  40. Papaleo F, Lipska BK, Weinberger DR (2012) Mouse models of genetic effects on cognition: relevance to schizophrenia. Neuropharmacology 62:1204–1220

    CAS  PubMed  Article  Google Scholar 

  41. Papaleo F, Sannino S, Piras F, Spalletta G (2015) Sex-dichotomous effects of functional COMT genetic variations on cognitive functions disappear after menopause in both health and schizophrenia. Eur Neuropsychopharmacol 25:2349–2363

    CAS  PubMed  Article  Google Scholar 

  42. Paterson IA, Davis BA, Durden DA, Juorio AV, Yu PH, Ivy G, Milgram W, Mendonca A, Wu P, Boulton AA (1995) Inhibition of MAO-B by (-)-deprenyl alters dopamine metabolism in the macaque (Macaca facicularis) brain. Neurochem Res 20:1503–1510

    CAS  PubMed  Article  Google Scholar 

  43. Popik P, Nikiforuk A (2015) Attentional set-shifting paradigm in the rat. Curr Protoc Neurosci 72: 9 51 1-13.

  44. Reches A, Fahn S (1984) Catechol-O-methyltransferase and Parkinson’s disease. Adv Neurol 40:171–179

    CAS  PubMed  Google Scholar 

  45. Risbrough V, Ji B, Hauger R, Zhou X (2014) Generation and characterization of humanized mice carrying COMT158 Met/Val alleles. Neuropsychopharmacology 39:1823–1832

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Robinson RG, Smith SM, Wolkenberg SE, Kandebo M, Yao L, Gibson CR, Harrison ST, Polsky-Fisher S, Barrow JC, Manley PJ, Mulhearn JJ, Nanda KK, Schubert JW, Trotter BW, Zhao Z, Sanders JM, Smith RF, McLoughlin D, Sharma S, Hall DL, Walker TL, Kershner JL, Bhandari N, Hutson PH, Sachs NA (2012) Characterization of non-nitrocatechol pan and isoform specific catechol-O-methyltransferase inhibitors and substrates. ACS Chem Neurosci 3:129–140

    CAS  PubMed  Article  Google Scholar 

  47. Sannino S, Gozzi A, Cerasa A, Piras F, Scheggia D, Manago F, Damiano M, Galbusera A, Erickson LC, De Pietri TD, Bifone A, Tsaftaris SA, Caltagirone C, Weinberger DR, Spalletta G, Papaleo F (2015) COMT genetic reduction produces sexually divergent effects on cortical anatomy and working memory in mice and humans. Cereb Cortex 25:2529–2541

    PubMed  Article  Google Scholar 

  48. Sannino S, Padula MC, Manago F, Schaer M, Schneider M, Armando M, Scariati E, Sloan-Bena F, Mereu M, Pontillo M, Vicari S, Contarini G, Chiabrera C, Pagani M, Gozzi A, Eliez S, Papaleo F (2017) Adolescence is the starting point of sex-dichotomous COMT genetic effects. Transl Psychiatry 7:e1141

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. Tammimaki A, Kaenmaki M, Kambur O, Kulesskaya N, Keisala T, Karvonen E, Garcia-Horsman JA, Rauvala H, Mannisto PT (2010) Effect of S-COMT deficiency on behavior and extracellular brain dopamine concentrations in mice. Psychopharmacology (Berl) 211:389–401

    Article  CAS  Google Scholar 

  50. Tenhunen J, Salminen M, Jalanko A, Ukkonen S, Ulmanen I (1993) Structure of the rat catechol-O-methyltransferase gene: separate promoters are used to produce mRNAs for soluble and membrane-bound forms of the enzyme. DNA Cell Biol 12:253–263

    CAS  PubMed  Article  Google Scholar 

  51. Tenhunen J, Salminen M, Lundstrom K, Kiviluoto T, Savolainen R, Ulmanen I (1994) Genomic organization of the human catechol O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 223:1049–1059

    CAS  PubMed  Article  Google Scholar 

  52. Tenhunen J, Ulmanen I (1993) Production of rat soluble and membrane-bound catechol O-methyltransferase forms from bifunctional mRNAs. Biochem J 296(Pt 3):595–600

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ (2004) Catechol-o-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 24:5331–5335

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. Valomon A, Holst SC, Borrello A, Weigend S, Muller T, Berger W, Sommerauer M, Baumann CR, Landolt HP (2018) Effects of COMT genotype and tolcapone on lapses of sustained attention after sleep deprivation in healthy young men. Neuropsychopharmacology 43:1599–1607

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. Wanneveich M, Jacqmin-Gadda H, Dartigues JF, Joly P (2018) Projections of health indicators for chronic disease under a semi-Markov assumption. Theor Popul Biol 119:83–90

    PubMed  Article  Google Scholar 

  56. Watkins P (2000) COMT inhibitors and liver toxicity. Neurology 55: S51-2; discussion S53-6.

  57. Wood RL, Worthington A (2017) Neurobehavioral abnormalities associated with executive dysfunction after traumatic brain injury. Front Behav Neurosci 11:195

    PubMed  PubMed Central  Article  Google Scholar 

  58. Yavich L, Forsberg MM, Karayiorgou M, Gogos JA, Mannisto PT (2007) Site-specific role of catechol-O-methyltransferase in dopamine overflow within prefrontal cortex and dorsal striatum. J Neurosci 27:10196–10209

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. Zhang G, Buchler IP, DePasquale M, Wormald M, Liao G, Wei H, Barrow JC, Carr GV (2019) Development of a PC12 cell based assay for screening catechol-O-methyltransferase inhibitors. ACS Chem Neurosci 10:4221–4226

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. Zhang Y, Feng S, Nie K, Zhao X, Gan R, Wang L, Zhao J, Tang H, Gao L, Zhu R, Wang L, Zhang Y (2016) Catechol-O-methyltransferase Val158Met polymorphism influences prefrontal executive function in early Parkinson’s disease. J Neurol Sci 369:347–353

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgments

The authors thank Michael Poslusney and Noelle White for technical assistance, Richard Brammer for statistical analysis of the microdialysis data, Elizabeth Tunbridge for advice on the ASST assay, and Daniel R. Weinberger for constructive comments on a draft of this manuscript.

Funding

This work was funded by the US National Institutes of Health grant R01MH107126 and The Lieber Institute for Brain Development.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Gregory V. Carr.

Ethics declarations

All procedures were approved by the local Animal Care and Use Committee and were in compliance with the Guide for the Care and Use of Laboratory Animals.

Conflict of interest

IPB and JCB are inventors on patents that include the novel COMT inhibitors (WO2016123576 and WO2017091818). HLR, RSK, LP, and SCC are employees of RenaSci Ltd. The remaining authors have nothing to disclose.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Byers, S., Buchler, I.P., DePasquale, M. et al. Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility. Psychopharmacology 237, 2695–2707 (2020). https://doi.org/10.1007/s00213-020-05566-0

Download citation

Keywords

  • Catechol-O-methyltransferase
  • Dopamine
  • Tolcapone
  • Cortex
  • Executive function
  • Microdialysis
  • Rat
  • Schizophrenia
  • Parkinson’s disease
  • Cognitive impairment