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

Byers, S.; Buchler, I. P.; DePasquale, M.; Rowley, H. L.; Kulkarni, R. S.; Pinder, L.; Kolobova, A.; Li, C.; Au, V.; Akuma, D.; Zhang, G.; Wei, H.; Cheetham, S. C.; Barrow, J. C.; Carr, G.

doi:10.1101/510040

bioRxiv · 10.1101/510040

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

Byers, S.·Buchler, I. P.·DePasquale, M.·Rowley, H. L.·Kulkarni, R. S.·Pinder, L.·Kolobova, A.·Li, C.·Au, V.·Akuma, D.·Zhang, G.·Wei, H.·Cheetham, S. C.·Barrow, J. C.·Carr, G.

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Abstract

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. To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel COMT inhibitors in a set of preclinical in vivo efficacy assays to determine their viability as potential clinical candidates. 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 dopamine metabolites, in cerebrospinal fluid (CSF) and the frontal cortex. Additionally, we found the LIBD-1 significantly improved cognitive flexibility in a rat attentional set-shifting assay (ASST), an effect previously seen with the COMT inhibitor tolcapone. 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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Byers, S., Buchler, I. P., DePasquale, M., Rowley, H. L., Kulkarni, R. S., Pinder, L., Kolobova, A., Li, C., Au, V., Akuma, D., Zhang, G., Wei, H., Cheetham, S. C., Barrow, J. C., Carr, G.. 2019-01-02. Novel, non-nitrocatechol COMT inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility. https://doi.org/10.1101/510040

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