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Biomolecules Sep 2023The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal...
The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers and , we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors.
Topics: Animals; Humans; Norepinephrine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins; Biological Transport; Structure-Activity Relationship; Norepinephrine; Ligands
PubMed: 37759815
DOI: 10.3390/biom13091415 -
Analytical Methods : Advancing Methods... Nov 2023Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological...
Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological symptoms. In the literature, there is no report of square wave voltammetric (SWV) methods being used for the determination of MOD. This study describes, for the first time, the construction and evaluation of the analytical performance of a novel sensor for ultrasensitive SWV detection of MOD. The sensor was constructed by integration of silver nanoparticles (Ag) on Mesna (MSN) layers over a pencil graphite electrode (PGE) surface. The interface and morphological characteristics of the fabricated Ag@MSN/PGE sensor were investigated cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). This sensor was found to enhance the electro-oxidation of MOD. The combination of Ag@MSN/PGE with SWV enabled the determination of MOD in its bulk form and in pharmaceutical and biological matrices at the nanomolar scale (LOD = 28.59 nM) with excellent recoveries. This study represents the first report describing an electrochemical procedure for MOD detection in human plasma. The established SWV method was also validated, and the results were consistent with ICH criteria. Finally, the presented SWV procedure provides a facile, sensitive, rapid, and cost-effective approach compared to other existing methods.
Topics: Humans; Metal Nanoparticles; Modafinil; Mesna; Silver; Electrochemical Techniques; Graphite
PubMed: 37847517
DOI: 10.1039/d3ay01401k -
Addiction & Health Feb 2024The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal... (Review)
Review
The likelihood of substance dependency in offspring is increased in cases when there is a family history of drug or alcohol use. Mothering is limited by maternal addiction because of the separation. Maternal separation (MS) leads to the development of behavioural and neuropsychiatric issues in the future. Despite the importance of this issue, empirical investigations of the influences of maternal substance use and separation on substance use problems in offspring are limited, and studies that consider both effects are rare. This study aims to review a few studies on the mechanisms, treatments, genetics, epigenetics, molecular and psychological alterations, and neuroanatomical regions involved in the dependence of offspring who underwent maternal addiction and separation. The PubMed database was used. A total of 95 articles were found, including the most related ones in the review. The brain's lateral paragigantocellularis (LPGi), nucleus accumbens (NAc), caudate-putamen (CPu), prefrontal cortex (PFC), and hippocampus, can be affected by MS. Dopamine receptor subtype genes, alcohol biomarker minor allele, and preproenkephalin mRNA may be affected by alcohol or substance use disorders. After early-life adversity, histone acetylation in the hippocampus may be linked to brain-derived neurotrophic factor (BDNF) gene epigenetics and glucocorticoid receptors (GRs). The adverse early-life experiences differ in offspring›s genders and rewire the brain›s dopamine and endocannabinoid circuits, making offspring more susceptible to dependence. Related psychological factors rooted in early-life stress (ELS) and parental substance use disorder (SUD). Treatments include antidepressants, histone deacetylase inhibitors, lamotrigine, ketamine, choline, modafinil, methadone, dopamine, cannabinoid 1 receptor agonists/antagonists, vitamins, oxytocin, tetrahydrocannabinol, SR141716A, and dronabinol. Finally, the study emphasizes the need for multifaceted strategies to prevent these outcomes.
PubMed: 38651025
DOI: 10.34172/ahj.2024.1478 -
Medicine Feb 2024Although patients with central disorders of hypersomnolence (CDH) exhibit characteristic symptoms of hypersomnia frequently, it takes 5 to 15 years from the onset for...
RATIONALE
Although patients with central disorders of hypersomnolence (CDH) exhibit characteristic symptoms of hypersomnia frequently, it takes 5 to 15 years from the onset for its diagnosis due to the lack of symptom recognition. Here, we present a case of idiopathic hypersomnia (IH), a CDH, wherein early diagnosis was aided by a video footage of a spontaneous sleep attack.
PATIENT CONCERNS
A 21-year-old man lost consciousness while driving and experienced an accident. He had complained of excessive daytime sleepiness (EDS) over half a year. During his hospitalization for close monitoring of the loss of consciousness, an in-room surveillance camera captured a 14-minutes long spontaneous sleep attack, during which he experienced general muscle weakness and loss of consciousness without warnings or convulsions leading to a fall from the bed. There were no abnormalities in vital signs.
DIAGNOSES
There was no significant cataplexy and less than 2 sleep-onset rapid eye movements (SOREM) in 2 sleep latency tests, with a mean sleep latency of 2.1 and 4.6 minutes. Other sleep deprivation syndromes were excluded from differential diagnosis and finally, a diagnosis of IH was confirmed according to the criteria of the Third Edition of the International Classification of Sleep Disorders. During the course of the disease, attention-deficit/hyperactive disorder (ADHD) and a gaming disorder also diagnosed.
INTERVENTIONS
Pharmacological treatment with modafinil was administered for IH and methylphenidate for ADHD. Cognitive behavioral therapy was performed for the gaming disorder.
OUTCOMES
The EDS improved, and sleep attacks were no longer observed. The disruption of daily life caused by the gaming disorder was also reduced.
LESSONS
Video recordings of sleep attacks are beneficial for identifying the cause of loss of consciousness. Home video recordings may be helpful in the early diagnosis of IH.
Topics: Humans; Male; Young Adult; Disorders of Excessive Somnolence; Idiopathic Hypersomnia; Modafinil; Sleep; Unconsciousness
PubMed: 38363934
DOI: 10.1097/MD.0000000000036782 -
Journal of Psychopharmacology (Oxford,... Sep 2023
Topics: Modafinil; Central Nervous System Stimulants; Benzhydryl Compounds
PubMed: 37435726
DOI: 10.1177/02698811231187127 -
Frontiers in Pharmacology 2023Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for screening of compounds, inspired by analytical methods quantifying gene...
Drug-induced Behavioral Signature Analysis (DBSA), is a machine learning (ML) method for screening of compounds, inspired by analytical methods quantifying gene enrichment in genomic analyses. When applied to behavioral data it can identify drugs that can potentially reverse behavioral symptoms in animal models of human disease and suggest new hypotheses for drug discovery and repurposing. We present a proof-of-concept study aiming to assess Drug-induced Behavioral Signature Analysis (DBSA) as a systematic approach for drug discovery for rare disorders. We applied Drug-induced Behavioral Signature Analysis to high-content behavioral data obtained with SmartCube, an automated phenotyping platform. The therapeutic potential of several dozen approved drugs was assessed for phenotypic reversal of the behavioral profile of a Huntington's Disease (HD) murine model, the Q175 heterozygous knock-in mice. The Drug-induced Behavioral Signature Analysis predictions were enriched for drugs known to be effective in the symptomatic treatment of Huntington's Disease, including bupropion, modafinil, methylphenidate, and several SSRIs, as well as the atypical antidepressant tianeptine. To validate the method, we tested acute and chronic effects of tianeptine (20 mg/kg) , using Q175 mice and wild type controls. In both experiments, tianeptine significantly rescued the behavioral phenotype assessed with the SmartCube platform. Our target-agnostic method thus showed promise for identification of symptomatic relief treatments for rare disorders, providing an alternative method for hypothesis generation and drug discovery for disorders with huge disease burden and unmet medical needs.
PubMed: 37560472
DOI: 10.3389/fphar.2023.1128562 -
Scientific Reports Nov 2023The use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have... (Randomized Controlled Trial)
Randomized Controlled Trial
The use of so-called 'smart drugs' such as modafinil to improve cognitive performance has recently attracted considerable attention. However, their side effects have limited user enthusiasm. Open-label placebo (OLP) treatment, i.e., inert treatments that are openly disclosed to individuals as having no active pharmacological ingredient, has been shown to improve various medical symptoms and conditions, including those related to cognitive performance. OLP treatment could therefore be an exciting alternative to pharmacological cognitive enhancers. Here, we used a randomized-controlled design to investigate the effect of a 21-day OLP treatment on several sub-domains of cognitive performance in N = 78 healthy volunteers. Subjective and objective measures of cognitive performance as well as different measures of well-being were obtained before and after the treatment period. Using a combination of classic Frequentist and Bayesian analysis approaches showed no additional benefit from OLP treatment in any of the subjective or objective measures of cognitive performance. Our study thus highlights possible limitations of OLP treatment in boosting cognitive performance in healthy volunteers. These findings are discussed in the light of expectancy-value considerations that may determine OLP efficacy.
Topics: Humans; Attention; Bayes Theorem; Cognition; Healthy Volunteers; Modafinil; Placebo Effect
PubMed: 37945662
DOI: 10.1038/s41598-023-45979-3 -
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 -
Diabetes Aug 2023Perifornical hypothalamus (PFH) orexin glucose-inhibited (GI) neurons that facilitate arousal have been implicated in hypoglycemia awareness. Mice lacking orexin exhibit...
Perifornical hypothalamus (PFH) orexin glucose-inhibited (GI) neurons that facilitate arousal have been implicated in hypoglycemia awareness. Mice lacking orexin exhibit narcolepsy, and orexin mediates the effect of the antinarcolepsy drug modafinil. Thus, hypoglycemia awareness may require a certain level of arousal for awareness of the sympathetic symptoms of hypoglycemia (e.g., tremors, anxiety). Recurrent hypoglycemia (RH) causes hypoglycemia unawareness. We hypothesize that RH impairs the glucose sensitivity of PFH orexin GI neurons and that modafinil normalizes glucose sensitivity of these neurons and restores hypoglycemia awareness after RH. Using patch-clamp recording, we found that RH enhanced glucose inhibition of PFH orexin GI neurons in male mice, thereby blunting activation of these neurons in low-glucose conditions. We then used a modified conditioned place preference behavioral test to demonstrate that modafinil reversed hypoglycemia unawareness in male mice after RH. Similarly, modafinil restored normal glucose sensitivity to PFH orexin GI neurons. We conclude that impaired glucose sensitivity of PFH orexin GI neurons plays a role in hypoglycemia unawareness and that normalizing their glucose sensitivity after RH is associated with restoration of hypoglycemia awareness. This suggests that the glucose sensitivity of PFH orexin GI neurons is a therapeutic target for preventing hypoglycemia unawareness.
Topics: Mice; Male; Animals; Orexins; Modafinil; Hypoglycemia; Glucose; Neurons; Diabetes Complications
PubMed: 36525384
DOI: 10.2337/db22-0639 -
Nature May 2024
Topics: Humans; Animals; Appetite; Obesity; Mice; Anti-Obesity Agents; Brain; Modafinil; Neural Pathways
PubMed: 38750199
DOI: 10.1038/d41586-024-01352-6