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

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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.

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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.

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Authors and Affiliations

  1. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA

    Spencer Byers, Ingrid P. Buchler, Michael DePasquale, Anna Kolobova, Cailian Li, Vinh Au, Daniel Akuma, Gongliang Zhang, Huijun Wei, James C. Barrow & Gregory V. Carr

  2. RenaSci Limited, Nottingham, UK

    Helen L. Rowley, Rajiv S. Kulkarni, Lucy Pinder & Sharon C. Cheetham

  3. Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Suite 300, 855 North Wolfe Street, Baltimore, Maryland, USA

    Huijun Wei, James C. Barrow & Gregory V. Carr

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  1. Spencer Byers
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  2. Ingrid P. Buchler
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  3. Michael DePasquale
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  14. James C. Barrow
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  15. Gregory V. Carr
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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.

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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

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