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.

Keywords: Catechol-O-methyltransferase; Cognitive impairment; Cortex; Dopamine; Executive function; Microdialysis; Parkinson’s disease; Rat; Schizophrenia; Tolcapone.

Figure 1.. COMT inhibitors.

The structures and in vitro potency values (rat COMT) for LIBD-1, LIBD-2, LIBD-3, and tolcapone. Additional pharmacokinetic information iv half-life (T_1/2) and oral bioavailability (F) is included for LIBD-2. These data for LIBD-1 and LIBD-2 are included in the Buchler et al., 2018 (compound 28) and Ernst et al., 2019 (compound 38), respectively. PK parameters were calculated based on 1 mg/kg iv (n = 3) and 10 mg/kg po (n = 3) doses.

Figure 2.. Effects of COMT inhibitors on DA and metabolites in the frontal cortex measured by microdialysis.

a DA concentration. None of the COMT inhibitors altered extracellular DA concentration. b HVA concentration. All of the COMT inhibitors decreased the extracellular HVA concentration. Tolcapone and LIBD-3 significantly decreased HVA for the 40–120-min time points while LIBD-1 significantly decreased HVA at the 100-min time point. c DOPAC concentration. All of the COMT inhibitors increased the extracellular DOPAC concentration. Tolcapone significantly increased DOPAC for the 40–120-min time points while LIBD-1 and LIBD-3 significantly increased DOPAC for the 60–120-min time points. n = 8 for vehicle, 7 for tolcapone, 8 for LIBD-1 and 8 for LIBD-3. Drug or vehicle was administered at t = 0. *p <0.05, **p <0.01, ***p < 0.001 compared to the vehicle-treated group at that time point.

Figure 3.. Effects of COMT inhibitors on behavior in the ASST.

a Tolcapone (n = 12/vehicle group and n = 11/tolcapone group b LIBD-1 (n = 24/vehicle group, n = 15/LIBD-1 30 mg/kg group, and n = 14/LIBD-1 100 mg/kg group). c LIBD-3 (n = 21/vehicle group, n = 14/LIBD-3 30 mg/kg group, and n = 10/ LIBD-3 100 mg/kg group). d Performance of select groups in the ED stage across independent experiments. These data were not analyzed together and are presented here only for visual comparison. The vehicle-treated group represents a pooled sample from the LIBD-1 and tolcapone cohorts. *p <0.05 and **p <0.01 compared to the vehicle-treated group in the stage. Stage abbreviations: SD = simple discrimination; CD= compound discrimination; CDr = compound discrimination reversal; ID = intradimensional discrimination; IDr = intradimensional discrimination reversal; ED = extradimensional discrimination; EDr = extradimensional discrimination reversal.