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International Journal of Molecular... Nov 2023-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue...
-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of -CE-123 and -modafinil. To address this objective, a precise liquid chromatography-high resolution mass spectrometry method was developed and partially validated. Neuropharmacokinetic parameters were assessed using the Combinatory Mapping Approach. Our findings reveal distinct differences between the two compounds. Notably, -CE-123 demonstrates a significantly superior extent of transport across the blood-brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (K) of 0.5, compared to -modafinil's K of 0.1. A similar pattern was observed for the transport across the blood-spinal cord barrier. Concerning the drug transport across cellular membranes, we observed that -CE-123 primarily localizes in the brain interstitial space, whereas -modafinil distributes more evenly across both sides of the plasma membrane of the brain's parenchymal cells (K). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with -CE-123 having a 9.3-fold faster metabolism compared to -modafinil. In summary, the combination of improved BBB transport and higher affinity of -CE-123 to dopamine transporters in comparison to -modafinil makes -CE-123 a promising candidate for further testing for the treatment of cognitive decline.
Topics: Benzhydryl Compounds; Brain; Central Nervous System; Dopamine Plasma Membrane Transport Proteins; Modafinil
PubMed: 38069277
DOI: 10.3390/ijms242316956 -
Frontiers in Physiology 2023Literature suggests pilots experience fatigue differently. So-called fatigue-resistant or -vulnerable individuals might also respond differently to countermeasures or...
Literature suggests pilots experience fatigue differently. So-called fatigue-resistant or -vulnerable individuals might also respond differently to countermeasures or stimulants. This study, which is part of a larger randomized controlled clinical trial, aims to investigate the effect of caffeine and modafinil on fatigue-resistant and -vulnerable pilots. This study included 32 healthy employees of the Royal Netherlands Air Force, who completed three test days, separated by at least 7 days. After a regular work day, the subjects were randomly administered either 300 mg caffeine, 200 mg modafinil or placebo at midnight. Hereafter the subjects performed the psychomotor vigilance test (PVT), vigilance and tracking test (VigTrack) and Stanford sleepiness scale (SSS) six times until 8 a.m. the next day. Subjects were ranked on the average number of lapses on the PVT during the placebo night and divided into three groups: fatigue-vulnerable (F), -intermediate (FINT) and -resistant (F), with 11, 10 and 11 subjects in each group, respectively. Area under the curve (AUC) of the PVT, VigTrack and SSS during the test nights were calculated, which were used in univariate factorial analysis of variance (ANOVA). Tukey's HSD tests were used to differentiate between the groups. A significant effect of treatment was found in the ANOVA of both PVT parameters, VigTrack mean reaction time and SSS. There was a statistically significant effect of fatigue group on all PVT parameters and VigTrack mean percentage omissions, where F and F scored better than F. There was a significant interaction effect between treatment and fatigue group for PVT number of lapses. This is congruent for the AUC analyses in which for all parameters (except for the SSS) the performance of the F group was consistently worse than that of the F and F groups. This study demonstrates that the performance of individuals with different fatigue tolerances are differently affected by simulants after a limited period of sleep deprivation. The classification of fatigue tolerance through PVT lapses when sleep deprived seems to be able to predict this.
PubMed: 38260091
DOI: 10.3389/fphys.2023.1303758 -
MedRxiv : the Preprint Server For... Jun 2024In a genome-wide association study (GWAS) of 685,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries and across diverse and admixed...
Genome-wide study of half a million individuals with major depression identifies 697 independent associations, infers causal neuronal subtypes and biological targets for novel pharmacotherapies.
In a genome-wide association study (GWAS) of 685,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries and across diverse and admixed ancestries, we identify 697 independent associations at 636 genetic loci, 293 of which are novel. Using fine-mapping and functional genomic datasets, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. Leveraging new single-cell gene expression data, we conducted a causal neural cell type enrichment analysis that implicated excitatory and inhibitory midbrain and forebrain neurons, peptidergic neurons, and medium spiny neurons in MD. Critically, our findings are enriched for the targets of antidepressants and provide potential antidepressant repurposing opportunities (e.g., pregabalin and modafinil). Polygenic scores (PGS) from European ancestries explained up to 5.7% of the variance in liability to MD in European samples and PGS trained using either European or multi-ancestry data significantly predicted case control status across all four diverse ancestries. These findings represent a major advance in our understanding of MD across global populations. We provide evidence that MD GWAS reveals known and novel biological targets that may be used to target and develop pharmacotherapies addressing the considerable unmet need for effective treatment.
PubMed: 38746223
DOI: 10.1101/2024.04.29.24306535 -
Neurology India 2023There is scarce literature on functional neuroimaging data in Kleine-Levin syndrome. The current case report presents the electrical and metabolic status of cortical...
There is scarce literature on functional neuroimaging data in Kleine-Levin syndrome. The current case report presents the electrical and metabolic status of cortical activity utilizing functional near-infrared spectroscopy (fNIRS) and quantitative electroencephalography (qEEG) before and after treatment of symptomatic phase of illness with modafinil.
Topics: Humans; Kleine-Levin Syndrome; Spectroscopy, Near-Infrared; Electroencephalography; Modafinil
PubMed: 38174469
DOI: 10.4103/0028-3886.391382 -
Nederlands Tijdschrift Voor Geneeskunde Apr 2024About 20% of adults experience excessive daytime sleepiness or severe fatigue. Causes include somatic conditions, psychiatric disorders, and medication or drug use....
About 20% of adults experience excessive daytime sleepiness or severe fatigue. Causes include somatic conditions, psychiatric disorders, and medication or drug use. Treatment depends on the underlying cause. If sleepiness persists despite optimal treatment of the underlying condition, exclusion of other causes, and behavioral interventions, wakefulness-promoting agents may be considered. However, no established pharmacological strategy exists for symptomatic treatment. Modafinil and stimulants like methylphenidate may offer some benefit based on experiences with narcolepsy or idiopathic hypersomnia. Studies in specific patient groups (e.g., multiple sclerosis, Parkinson's disease, traumatic brain injury, cancer-related fatigue) show variable results. The use of wakefulness-promoting agents is discouraged for addressing unexplained fatigue, as seen in the context of chronic fatigue syndrome.
Topics: Adult; Humans; Wakefulness-Promoting Agents; Central Nervous System Stimulants; Modafinil; Behavior Therapy; Brain Injuries, Traumatic
PubMed: 38630073
DOI: No ID Found -
ChemSusChem Jun 2024The sulfoxide moiety is one of the most commonly utilized groups in pharmaceutical and industrial chemistry. The need for sustainability and easy accessibility to...
The sulfoxide moiety is one of the most commonly utilized groups in pharmaceutical and industrial chemistry. The need for sustainability and easy accessibility to sulfoxide moieties is deemed necessary, due to its ubiquity in natural products and potentially pharmaceutically active compounds. In this context, we report herein a sustainable, aerobic and environmentally friendly photochemical protocol based on the use of a benzothioxathene imide as the photocatalyst to selectively oxidise sulfides under mild irradiation (456 nm), in very low catalyst loading (0.01 mol%) and on water. In addition, to demonstrate the compatibility of our protocol with wide scope of substrates, the latter was successfully applied to the synthesis of the biologically-active Sulforaphane and Modafinil.
PubMed: 38867402
DOI: 10.1002/cssc.202400903 -
Pharmacology, Biochemistry, and Behavior May 2024Caffeine and modafinil are used to reverse effects of sleep deprivation. Nicotinic alpha-7 receptor and AMPA receptor positive allosteric modulators (PAM) are also...
OBJECTIVE
Caffeine and modafinil are used to reverse effects of sleep deprivation. Nicotinic alpha-7 receptor and AMPA receptor positive allosteric modulators (PAM) are also potential substances in this context. Our objective is to evaluate the effects of caffeine, modafinil, AVL-3288 (nicotinic alpha-7 PAM) and CX516 (AMPA receptor PAM) on cognition and mood in a model of sleep deprivation.
METHOD
Modified multiple platform model is used to sleep-deprive mice for 24 days, for 8 h/day. Vehicle, Modafinil (40 mg/kg), Caffeine (5 mg/kg), CX516 (10 mg/kg), and AVL3288 (1 mg/kg) were administered intraperitoneally daily. A cognitive test battery was applied every six days for four times. The battery that included elevated plus maze, novel object recognition, and sucrose preference tests was administered on consecutive days.
RESULTS
Sleep deprivation decreased novel object recognition skill, but no significant difference was found in anxiety and depressive mood. Caffeine administration decreased anxiety-like behavior in short term, but this effect disappeared in chronic administration. Caffeine administration increased memory performance in chronic period. AVL group showed better memory performance in short term, but this effect disappeared in the rest of experiment. Although, in the modafinil group, no significant change in mood and memory was observed, anhedonia was observed in the chronic period in vehicle, caffeine and modafinil groups, but not in AVL-3288 and CX-516 groups.
CONCLUSION
Caffeine has anxiolytic effect in acute administration. The improvement of memory in chronic period may be associated with the neuroprotective effects of caffeine. AVL-3288 had a short-term positive effect on memory, but tolerance to these effects developed over time. Furthermore, no anhedonia was observed in AVL-3288 and CX516 groups in contrast to vehicle, caffeine and modafinil groups. This indicates that AVL-3288 and CX516 may show protective effect against depression.
PubMed: 38823543
DOI: 10.1016/j.pbb.2024.173793 -
The European Journal of Neuroscience May 2024Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual...
Psychostimulant use disorders (PSUD) are prevalent; however, no FDA-approved medications have been made available for treatment. Previous studies have shown that dual inhibitors of the dopamine transporter (DAT) and sigma receptors significantly reduce the behavioral/reinforcing effects of cocaine, which have been associated with stimulation of extracellular dopamine (DA) levels resulting from DAT inhibition. Here, we employ microdialysis and fast scan cyclic voltammetry (FSCV) procedures to investigate the effects of dual inhibitors of DAT and sigma receptors in combination with cocaine on nucleus accumbens shell (NAS) DA dynamics in naïve male Sprague Dawley rats. In microdialysis studies, administration of rimcazole (3, 10 mg/kg; i.p.) or its structural analog SH 3-24 (1, 3 mg/kg; i.p.), compounds that are dual inhibitors of DAT and sigma receptors, significantly reduced NAS DA efflux stimulated by increasing doses of cocaine (0.1, 0.3, 1.0 mg/kg; i.v.). Using the same experimental conditions, in FSCV tests, we show that rimcazole pretreatments attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Under the same conditions, JJC8-091, a modafinil analog and dual inhibitor of DAT and sigma receptors, similarly attenuated cocaine-induced stimulation of evoked NAS DA release but produced no additional effect on DA clearance rate. Our results provide the neurochemical groundwork towards understanding actions of dual inhibitors of DAT and sigma receptors on DA dynamics that likely mediate the behavioral effects of psychostimulants like cocaine.
Topics: Animals; Nucleus Accumbens; Receptors, sigma; Male; Dopamine Plasma Membrane Transport Proteins; Dopamine; Cocaine; Rats, Sprague-Dawley; Rats; Dopamine Uptake Inhibitors; Piperidines; Benzhydryl Compounds; Microdialysis; Modafinil
PubMed: 38444104
DOI: 10.1111/ejn.16293 -
Biomolecules Jun 2024Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead...
Modafinil analogs with either a sulfoxide or sulfide moiety have improved binding affinities at the human dopamine transporter (hDAT) compared to modafinil, with lead sulfoxide-substituted analogs showing characteristics of atypical inhibition (e.g., JJC8-091). Interestingly, the only distinction between sulfoxide and sulfide substitution is the presence of one additional oxygen atom. To elucidate why such a subtle difference in ligand structure can result in different typical or atypical profiles, we investigated two pairs of analogs. Our quantum mechanical calculations revealed a more negatively charged distribution of the electrostatic potential surface of the sulfoxide substitution. Using molecular dynamics simulations, we demonstrated that sulfoxide-substituted modafinil analogs have a propensity to attract more water into the binding pocket. They also exhibited a tendency to dissociate from Asp79 and form a new interaction with Asp421, consequently promoting an inward-facing conformation of hDAT. In contrast, sulfide-substituted analogs did not display these effects. These findings elucidate the structural basis of the activity cliff observed with modafinil analogs and also enhance our understanding of the functionally relevant conformational spectrum of hDAT.
Topics: Modafinil; Dopamine Plasma Membrane Transport Proteins; Humans; Molecular Dynamics Simulation; Binding Sites; Dopamine Uptake Inhibitors; Structure-Activity Relationship; Protein Binding
PubMed: 38927116
DOI: 10.3390/biom14060713 -
Clinical Gastroenterology and... Mar 2024We found Moulton et al's illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly...
We found Moulton et al's illustrative case series of 10 patients with inflammatory bowel disease (IBD) and chronic fatigue, all presenting with depression, particularly interesting. Among the patients, 8 previously had undergone treatment with multiple psychotropic medications, and 2 had active IBD as indicated by increased fecal calprotectin levels. Remarkably, all 10 patients responded positively to open-label treatment with modafinil, a central nervous system stimulant that blocks dopamine reuptake transport, which resulted in an impressive improvement in their fatigue symptoms. At baseline, the self-reported mean fatigue score was 16, measured on the IBD Fatigue Assessment Scale (IBD-FAS), which ranges up to 20, and with levels higher than 11 indicating severe fatigue. After 6 months of modafinil treatment, the mean fatigue score was 6.7..
PubMed: 38508480
DOI: 10.1016/j.cgh.2024.03.002