Identification and optimization of nitrophenolic analogues as dopamine metabolic enzyme inhibitors for the treatment of Parkinson's disease.

Progressive loss of dopaminergic neurons leads to the depletion of the striatal neurotransmitter dopamine, which is the main cause of Parkinson's disease (PD) motor symptoms. Simultaneous inhibition of the two key dopamine metabolic enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase B (MAO-B), could potentially be a breakthrough in achieving clinical efficacy. Representative compound C12 exhibits good COMT inhibitory activity (IC50 = 0.37 µM), metal chelation ability, and BBB permeability. Furthermore, results from in vivo biological activity evaluations indicate that C12 can improve dopamine levels and ameliorate MPTP-induced PD symptoms in mice. Preliminary in vivo and in vitro study results highlight the potential of compound C12 in PD treatment.

Discovery of thiazole salt AChE inhibitors and development of thiamine disulfide prodrugs targeting the central nervous system.

The selective AChE inhibitor donepezil has been approved by the FDA as a first-line drug for the treatment of mild to moderate AD. However, many peripheral side effects were observed in patients taking donepezil. Our main objective here is to provide insight into the opportunities and challenges associated with development of AChE inhibitors with high brain exposure and low peripheral side effects. In this study, we have for the first time revealed a series of novel thiazole salt AChE inhibitors, which exhibit a nanomolar inhibitory effect on human AChE. We further developed thiamine disulfide prodrugs based on optimized thiazole salt AChE inhibitors, which are reduced in the brain to form thiazole salt AChE inhibitors. In vivo experiments have confirmed that the representative prodrug Tap4 (i.p., 10 mg/kg) can be converted into the thiazole salt AChE inhibitor Tat2 and shows high brain exposure, reaching 500 ng/g. Further, the inhibitory effect of the prodrug Tap4 on AChE is obviously stronger in the brain than that on intestinal AChE of ICR mice. Our study provides a possible basis for centrally targeted thiazole salt inhibitors in the treatment of neurodegenerative diseases.

Significantly Increased Public Interest in Major Depressive Disorder During the COVID-19 Pandemic: Insights From a Google Trends Analysis.

Background As early as before the coronavirus disease 2019 (COVID-19) pandemic, nearly one billion people worldwide suffered from mental health problems. Of all the mental health conditions, major depressive disorder (MDD) is the leading cause of global health-related burden. During the COVID-19 pandemic, many uncertain factors affecting mental health accumulated, such as virus transmission, blockade and ban, public transport restrictions, closure of schools and enterprises, and reduction of social interaction, which led to an increase in the potential risk of MDD, further increasing the global health-related burden. Methodology To better clarify the public interest in major depressive disorder during the COVID-19 pandemic, a Google Trends analysis was employed with data from December 2019 to December 2021, taking the cumulative diagnosis rate and cumulative mortality rate of COVID-19 as the reference standard, The changes in public interest and behavior in online searching for major depressive disorder in the three countries most affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus (i.e. the United States, Brazil, and India) were evaluated. Results We observed that during the COVID-19 pandemic, public interest in major depressive disorder increased significantly on the Internet. At the same time, compared with the United States, this upward trend is more prominent in India and Brazil. The study found that the major depressive disorder search index of the United States reached the maximum at the end of September 2021, the major depressive disorder search index of Brazil reached the maximum at the beginning of July 2021, and the major depressive disorder search index of India reached the maximum at the beginning of June 2021. The above time nodes are the first turning point of decline after the continuous surge of COVID-19 confirmed cases in the United States, Brazil, and India, indicating that there is an important time correlation between the surge of COVID-19 cases and the public online search term major depressive disorder. Conclusion The Google Trends analysis shows that public interest in major depressive disorder is on the rise under the COVID-19 pandemic and that COVID-19 may be associated with MDD. These findings deserve further exploration, especially as a growing body of research reports suggests that the COVID-19 pandemic has led to a surge in the prevalence of MDD. The epidemic alerts the vast majority of countries to urgently strengthen mental health systems and provide patients with the necessary interventions based on the determinants of poor mental health.

Discovery of 2-(cyclopropanecarboxamido)-N-(5-((1-(4-fluorobenzyl)piperidin-4-yl)methoxy)pyridin-3-yl)isonicotinamide as a potent dual AChE/GSK3ß inhibitor for the treatment of Alzheimer's disease: Significantly increasing the level of acetylcholine in the brain without affecting that in intestine.

Acetylcholinesterase (AChE) inhibitors are currently the first-line drugs approved by the FDA for the treatment of Alzheimer's disease (AD). However, a short effective-window limits their therapeutic benefits. Clinical studies have confirmed that the combination of AChE inhibitors and neuroprotective agents exhibits better anti-AD effects. We have previously reported that the dual AChE/GSK3ß (Glycogen synthase kinase 3ß) modulators have both neuroprotective effects and cognitive impairment-improvement effects. In this study, we characterized a new backbone of the AChE/GSK3ß inhibitor 11c. It was identified as a highly potent AChE inhibitor and was found superior to donepezil, the first-line drug for the treatment of AD. In vivo studies confirmed that 11c significantly inhibited the activity of AChE in the brain but had little effect on the activity of AChE in the intestine. This advantage of 11c was expected to reduce the peripheral side effects caused by donepezil. Furthermore, biomarker studies have shown that 11c also improved the levels of acetylcholine and synaptophysin in the brain and exhibited neuroprotective effects. Preliminary in vivo and in vitro research results underline the exciting potential of compound 11c in the treatment of AD.