Novel, non-nitrocatechol catechol- O -methyltransferase inhibitors modulate dopamine neurotransmission in the frontal co
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ORIGINAL INVESTIGATION
Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility Spencer Byers 1 & Ingrid P. Buchler 1 & Michael DePasquale 1 & Helen L. Rowley 2 & Rajiv S. Kulkarni 2 & Lucy Pinder 2 & Anna Kolobova 1 & Cailian Li 1 & Vinh Au 1 & Daniel Akuma 1 & Gongliang Zhang 1 & Huijun Wei 1,3 & Sharon C. Cheetham 2 & James C. Barrow 1,3 & Gregory V. Carr 1,3 Received: 13 March 2019 / Accepted: 20 May 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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. Keywords Catechol-O-methyltransferase . Dopamine . Tolcapone . Cortex . Executive function . Microdialysis . Rat . Schizophrenia . Parkinson’s disease . Cognitive impairment
Introduction
* Gregory V. Carr [email protected] 1
Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA
2
RenaSci Limited, Nottingham, UK
3
Department of Pharmacology and Molecular Sciences, Johns Hopkins School of Medicine, Suite 300, 855 North Wolfe Street, Baltimore, Maryland, USA
Cognitive impairment is a core feature of many neurological and psychiatric disorders and the severity of the impairment is directly correlated with functional outcomes for patients (Gratwicke et a
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