Reuptake Inhibitors Research Articles

Dopaminergic Modulation and Computational ADMET Insights for the Antidepressant-like Effect of N-(3-(Phenylselanyl)prop-2-yn-1-yl)benzamide.

The compound N-(3-(phenylselanyl)prop-2-yn-1-yl)benzamide (SePB), which combines a selenium atom and a benzamide nucleus in an organic structure, has demonstrated a fast antidepressant-like effect in mice. This action is influenced by the serotonergic system and represents a promising development in the search for novel antidepressant drugs to treat major depressive disorder (MDD), which often resists conventional treatments. This study aimed to further explore the mechanism underlying the antidepressant-like effect of SePB by investigating the involvement of the dopaminergic and noradrenergic systems in the tail suspension test (TST) in mice and evaluating its pharmacokinetic profile in silico. Preadministration of the dopaminergic antagonists haloperidol (0.05 mg/kg, intraperitoneally (i.p.)), a nonselective antagonist of dopamine (DA) receptors, SCH23390 (0.01 mg/kg, subcutaneously (s.c.)), a D1 receptor antagonist, and sulpiride (50 mg/kg, i.p.), a D2/3 receptor antagonist, before SePB (10 mg/kg, intragastrically (i.g.)) prevented the anti-immobility effect of SePB in the TST, demonstrating that these receptors are involved in the antidepressant-like effect of SePB. Administration of the noradrenergic antagonists prazosin (1 mg/kg, i.p.), an α1-adrenergic antagonist, yohimbine (1 mg/kg, i.p.), an α2-adrenergic antagonist, and propranolol (2 mg/kg, i.p.), a β-adrenergic antagonist, did not block the antidepressant-like effect of SePB on TST, indicating that noradrenergic receptors are not involved in this effect. Additionally, the coadministration of SePB and bupropion (a noradrenaline/dopamine reuptake inhibitor) at subeffective doses (0.1 and 3 mg/kg, respectively) produced antidepressant-like effects. SePB also demonstrated good oral bioavailability and low toxicity in computational absorption, distribution, metabolism, excretion, and toxicity (ADMET) analyses. These findings suggest that SePB has potential as a new antidepressant drug candidate with a particular focus on the dopaminergic system.

Rebound activation of 5-HT neurons following SSRI discontinuation

Cessation of therapy with a selective serotonin (5-HT) reuptake inhibitor (SSRI) is often associated with an early onset and disabling discontinuation syndrome, the mechanism of which is surprisingly little investigated. Here we determined the effect on 5-HT neurochemistry of discontinuation from the SSRI paroxetine. Paroxetine was administered repeatedly to mice (once daily, 12 days versus saline controls) and then either continued or discontinued for up to 5 days. Whereas brain tissue levels of 5-HT and/or its metabolite 5-HIAA tended to decrease during continuous paroxetine, levels increased above controls after discontinuation, notably in hippocampus. In microdialysis experiments continuous paroxetine elevated hippocampal extracellular 5-HT and this effect fell to saline control levels on discontinuation. However, depolarisation (high potassium)-evoked 5-HT release was reduced by continuous paroxetine but increased above controls post-discontinuation. Extracellular hippocampal 5-HIAA also decreased during continuous paroxetine and increased above controls post-discontinuation. Next, immunohistochemistry experiments found that paroxetine discontinuation increased c-Fos expression in midbrain 5-HT (TPH2 positive) neurons, adding further evidence for a hyperexcitable 5-HT system. The latter effect was recapitulated by 5-HT1A receptor antagonist administration although gene expression analysis could not confirm altered expression of 5-HT1A autoreceptors following paroxetine discontinuation. Finally, in behavioural experiments paroxetine discontinuation increased anxiety-like behaviour, which partially correlated in time with the measures of increased 5-HT function. In summary, this study reports evidence that, across a range of experiments, SSRI discontinuation triggers a rebound activation of 5-HT neurons. This effect is reminiscent of neural changes associated with various psychotropic drug withdrawal states, suggesting a common unifying mechanism.

A novel reuptake inhibitor, IP2015, induces erection by increasing central dopamine and peripheral nitric oxide release.

An estimated 40% of patients with erectile dysfunction have a poor prognosis for improvement with currently available treatments. The present study investigated whether a newly developed monoamine transport inhibitor, IP2015, improves erectile function. We investigated the effects of IP2015 on monoamine uptake and binding, erectile function in rats and diabetic mice and the effect on corpus cavernosum contractility. IP2015 inhibited the uptake of 5-HT, noradrenaline and dopamine by human monoamine transporters expressed in cells and in rat brain synaptosomes. Intracavernosal pressure measurement in anaesthetized rats revealed that IP2015 dose-dependently increased the number and the duration of spontaneous erections. Whereas pretreatment with the dopamine D2-like receptor antagonists, clozapine and (-)-sulpiride, or cutting the cavernosal nerve inhibited IP2015-induced erectile responses, the phosphodiesterase type 5 inhibitor sildenafil further enhanced the IP2015-mediated increase in intracavernosal pressure. IP2015 also increased the number of erections in type 2 diabetic db/db mice. Direct intracavernosal injection of IP2015 increased penile pressure, and in corpus cavernosum strips, IP2015 induced concentration-dependent relaxations. These relaxations were enhanced by sildenafil and blunted by endothelial cell removal, a nitric oxide synthase inhibitor, NG-nitro-l-arginine and a D1-like receptor antagonist, SCH23390. Quantitative polymerase chain reaction (qPCR) showed the expression of the dopamine transporter in the rat corpus cavernosum. Our findings suggest that IP2015 stimulates erectile function by a central mechanism involving dopamine reuptake inhibition and direct NO-mediated relaxation of the erectile tissue. This novel multi-modal mechanism of action could offer a new treatment approach to erectile dysfunction.

Enhancing the action of serotonin by three different mechanisms prevents spontaneous seizure-induced mortality in Dravet mice.

Sudden unexpected death in epilepsy (SUDEP) is an underestimated complication of epilepsy. Previous studies have demonstrated that enhancement of serotonergic neurotransmission suppresses seizure-induced sudden death in evoked seizure models. However, it is unclear whether elevated serotonin (5-HT) function will prevent spontaneous seizure-induced mortality (SSIM), which is characteristic of human SUDEP. We examined the effects of 5-HT-enhancing agents that act by three different pharmacological mechanisms on SSIM in Dravet mice, which exhibit a high incidence of SUDEP, modeling human Dravet syndrome. Dravet mice of both sexes were evaluated for spontaneous seizure characterization and changes in SSIM incidence induced by agents that enhance 5-HT-mediated neurotransmission. Fluoxetine (a selective 5-HT reuptake inhibitor), fenfluramine (a 5-HT releaser and agonist), SR 57227 (a specific 5-HT3 receptor agonist), or saline (vehicle) was intraperitoneally administered over an 8-day period in Dravet mice, and the effect of these treatments on SSIM was examined. Spontaneous seizures in Dravet mice generally progressed from wild running to tonic seizures with or without SSIM. Fluoxetine at 30 mg/kg, but not at 20 or 5 mg/kg, significantly reduced SSIM compared with the vehicle control. Fenfluramine at 1-10 mg/kg, but not .2 mg/kg, fully protected Dravet mice from SSIM, with all mice surviving. Compared with the vehicle control, SR 57227 at 20 mg/kg, but not at 10 or 5 mg/kg, significantly lowered SSIM. The effect of these drugs on SSIM was independent of sex. Our data demonstrate that elevating serotonergic function by fluoxetine, fenfluramine, or SR 57227 significantly reduces or eliminates SSIM in Dravet mice in a sex-independent manner. These findings suggest that deficits in serotonergic neurotransmission likely play an important role in the pathogenesis of SSIM, and fluoxetine and fenfluramine, which are US Food and Drug Administration-approved medications, may potentially prevent SUDEP in at-risk patients.

A systematic review of effectiveness and safety of some herbal compounds as treatment for primary insomnia

Introduction Sleep related disorders affect around 30% of people all over the world, and evidence shows that 10% require therapeutic intervention. Insomnia represents the most common disturbance of sleep, defined as the experience of poor sleep for at least 1 month. Most of primary insomnia can be prevented by a proper lifestyle and sleep hygiene rules. Regardless, hypnotic drugs and widely prescribed, and most times, long-term used, which is not recommended because of its negative side effects.ObjectivesReview the scientific evidence about effectiveness of plant extracts for insomnia, natural products with practically no side-effects, and thus be possible to reduce or even avoid the use of hypnotic drugs.MethodsThe Medline database through the Pubmed search engine was used with the following keywords: “insomnia” and “herbal compounds”.ResultsValerian activity on sleep disturbances has been attributed to the presence of isovaleric acids and valepotriates with reported calming action and GABA reuptake inhibition with sedative effects. Considering the data presented in the literature, despite controversial and conflicting, several studies showed that valerian (160-600mg/day) improved sleep quality and reduced sleep latency and duration; also valerian seems more effective for chronic insomnia than acute episodes.Hop has different properties: calming, sleep inducing, gastric secretion stimulating and spasmolytic.Increasing GABAergic activity seems to be the main mechanism of action, thus inhibiting the central nervous system and also has demonstrated binding affinities to some of the melatonin and serotonin receptor. It’s sedative characteristics have been confirmed in a clinical trial in association with valerian, where sleep latency and quality were improved. However, monotherapy studies showed no relevant effectiveness in sleep.Kava Kava plant showed promising results, in rats and humans, with decrease sleep latency, better sleep quality and recuperation after sleep. However, raised concern about its potential of hepatotoxicity.There is also promising evidence of the lavender efficacy for sleep disorders in a wide variety of populations and diseases, it was actually mentioned to be as effective as lorazepam in adults with anxiety and sleeping problems. With studies with dose of 80mg it was observed a reduction in sleep awakenings, sleep duration and overall sleep quality and anxiety.Conclusions There is a clear preference from the patient to natural compounds, and with almost nonexistent side effects, some herbal derivates are showed to have positive effectiveness in mild insomnia, but nonetheless much more studies on this field are needed.Disclosure of InterestNone Declared

Acute pain syndromes in injuries to the nerves and plexuses of the limbs

Injuries of peripheral nerves and plexuses cause serious disorders in the affected limbs. Unfortunately, the frequency of nerve injuries and limb plexuses is steadily increasing in our country, due to hostilities, which emphasizes the extreme relevance of this pathology. The aim of the review is to consider the current data on pathophysiological mechanisms, clinical manifestations, and treatment of acute pain syndromes in patients with injuries of peripheral nerves and limb plexuses. Materials and methods. Scientific databases PubMed, Google Scholar, Scopus, Cochrane Library, as well as the materials of the International Association for the study of pain were used to search for sources of research information. The main studies were found in Pubmed, Google Scholar and materials of the International Association for the study of pain and made up 191 sources of information, 150 of which were excluded from the review due to insufficient data on pathophysiological mechanisms, clinical manifestations, and treatment of pain syndromes in patients with damage to the nerves and plexuses of the limbs, thus 41 sources of information formed the basis of the review. Results: Brachial plexus and peripheral nerve injuries can be associated with any combination of nociceptive, neuropathic, phantom limb pain, and even complex regional pain syndromes. Acute neuropathic pain is an under-recognized condition, often difficult to treat and can progress to persistent pain and disability. Neuropathic pain develops because the main damage affects the somatosensory system. It is caused by peripheral nerve damage and associated changes in the central nervous system. The first line of pharmacological treatment for neuropathic pain according to current guidelines is anticonvulsant drugs that affect neuronal calcium channels, as well as tri- and tetracyclic antidepressants and selective serotonin/norepinephrine reuptake inhibitors. Conclusions: At the current stage, progress has been made in understanding the mechanisms of development of the pathological condition and in the development of therapeutic approaches, however, the chronicity of pain syndrome in patients with damage to the nerves and plexuses of the limbs is still high, which requires further research to develop complex pathogenetic therapy and better understanding of the mechanisms pain in this category of patients

The hippocampal salt-inducible kinase 2-CREB-regulated transcription co-activator 1 system mediates the antidepressant actions of paroxetine in mice

The hippocampal salt-inducible kinase 2 (SIK2)-CREB-regulated transcription co-activator 1 (CRTC1) system has been demonstrated to participate in not only the pathogenesis of depression but also the antidepressant mechanisms of several antidepressant medications including fluoxetine, paroxetine, and mirtazapine. Like fluoxetine, paroxetine is also a widely used selective serotonin (5-HT) reuptake inhibitor (SSRI). Recent studies have indicated that paroxetine also modulates several pharmacological targets other than the 5-HT system. Here, we speculate that paroxetine regulates the hippocampal SIK2-CRTC1 system. Chronic stress models of depression, various behavioral tests, western blotting, co-immunoprecipitation, quantitative real-time reverse transcription PCR, and genetic knockdown were used together in the present study. Our results show that the antidepressant actions of paroxetine in mice models of depression were accompanied by its preventing effects against chronic stress on hippocampal SIK2, CRTC1, and CRTC1-CREB binding. In contrast, genetic knockdown of hippocampal CRTC1 notably abrogated the antidepressant effects of paroxetine in mice. In summary, regulating hippocampal SIK2 and CRTC1 participates in the antidepressant mechanism of paroxetine, extending the knowledge of its pharmacological targets.

Design, synthesis, and biological evaluation of aralkyl piperazine and piperidine derivatives targeting SSRI/5-HT1A/5-HT7

Serotonin reuptake inhibition combined with the action targeting 5-hydroxytryptamine receptor subtypes can serve as a potential target for the development of antidepressant drugs. Herein a series of new aralkyl piperazines and piperidines were designed and synthesized by the structural modifications of the previously discovered aralkyl piperidine compound 1, targeting SSRI/5-HT1A/5-HT7. The results exhibited that compound 5a showed strong binding to 5-HT1A and 5-HT7 (Ki of 0.46 nM, 2.7 nM, respectively) and a high level of serotonin reuptake inhibition (IC50 of 1.9 nM), all of which were significantly elevated compared to 1. In particular, compound 5a showed weaker inhibitory activity against hERG than 1, and demonstrated good stability in liver microsomes in vitro. The preliminary screening using FST indicated that orally administered 5a, at a high dose, could reduce immobility time in mice markedly, indicating potential antidepressant activity.

RTN2 deficiency results in an autosomal recessive distal motor neuropathy with lower limb spasticity.

Heterozygous RTN2 variants have been previously identified in a limited cohort of families affected by autosomal dominant spastic paraplegia (SPG12-OMIM:604805) with a variable age of onset. Nevertheless, the definitive validity of SPG12 remains to be confidently confirmed due to the scarcity of supporting evidence. In this study, we identified and validated seven novel or ultra-rare homozygous loss-of-function RTN2 variants in 14 individuals from seven consanguineous families with distal hereditary motor neuropathy (dHMN) using exome, genome and Sanger sequencing coupled with deep-phenotyping. All affected individuals (seven males and seven females, aged 9-50 years) exhibited weakness in the distal upper and lower limbs, lower limb spasticity and hyperreflexia, with onset in the first decade of life. Nerve conduction studies revealed axonal motor neuropathy with neurogenic changes in the electromyography. Despite a slowly progressive disease course, all patients remained ambulatory over a mean disease duration of 19.71 ± 13.70 years. Characterization of Caenorhabditis elegans RTN2 homologous loss-of-function variants demonstrated morphological and behavioural differences compared with the parental strain. Treatment of the mutant with an endoplasmic/sarcoplasmic reticulum Ca2+ reuptake inhibitor (2,5-di-tert-butylhydroquinone) rescued key phenotypic differences, suggesting a potential therapeutic benefit for RTN2-disorder. Despite RTN2 being an endoplasmic reticulum (ER)-resident membrane shaping protein, our analysis of patient fibroblast cells did not find significant alterations in ER structure or the response to ER stress. Our findings delineate a distinct form of autosomal recessive dHMN with pyramidal features associated with RTN2 deficiency. This phenotype shares similarities with SIGMAR1-related dHMN and Silver-like syndromes, providing valuable insights into the clinical spectrum and potential therapeutic strategies for RTN2-related dHMN.

Update on Treating Painful Diabetic Peripheral Neuropathy: A Review of Current US Guidelines with a Focus on the Most Recently Approved Management Options.

Painful diabetic peripheral neuropathy (DPN) is a highly prevalent and disabling complication of diabetes that is often misdiagnosed and undertreated. The management of painful DPN involves treating its underlying cause via lifestyle modifications and intensive glucose control, targeting its pathogenesis, and providing symptomatic pain relief, thereby improving patient function and health-related quality of life. Four pharmacologic options are currently approved by the US Food and Drug Administration (FDA) to treat painful DPN. These include three oral medications (duloxetine, pregabalin, and tapentadol extended release) and one topical agent (capsaicin 8% topical system). More recently, the FDA approved several spinal cord stimulation (SCS) devices to treat refractory painful DPN. Although not FDA-approved specifically to treat painful DPN, tricyclic antidepressants, serotonin/norepinephrine reuptake inhibitors, gabapentinoids, and sodium channel blockers are common first-line oral options in clinical practice. Other strategies may be used as part of individualized comprehensive pain management plans. This article provides an overview of the most recent US guidelines for managing painful DPN, with a focus on the two most recently approved treatment options (SCS and capsaicin 8% topical system), as well as evidence for using FDA-approved and guideline-supported drugs and devices. Also discussed are unmet needs for this patient population, and evidence for potential future treatments for painful DPN, including drugs with novel mechanisms of action, electrical stimulation devices, and nutraceuticals.

Psychiatric Diagnoses and Psychotropic Drug Usage in Gender-Affirming Voice Surgery Patients

ObjectivesTo describe the burden of psychiatric illness and psychotropic medication usage among the subset of transgender patients who undergo gender affirming laryngeal surgery and describe some of the most commonly encountered conditions experienced by this population Methods: An IRB approved chart review was conducted for the eighteen patients who have undergone gender affirming laryngeal procedures from August 2019 to June 2022 performed at a single institution. Patient demographic data, treatment details, and psychiatric diagnoses and prescriptions for psychotropic medications were recorded. ResultsOf the eighteen patients who underwent gender affirming laryngeal surgery at this institution, sixteen patients underwent these operations as part of a transition from male to female gender, while two patients were transitioning from female to male gender. In this cohort, thirteen patients were diagnosed with a psychiatric comorbidity (72.2%). Of these patients, eleven were prescribed at least one psychotropic medication (61.1%). The most common psychiatric illnesses encountered in these patients were depression, anxiety, and post-traumatic stress disorder. Ten patients were diagnosed with more than one psychiatric comorbidity (55.6%). The most commonly prescribed psychotropic drugs were selective serotonin/norepinephrine reuptake inhibitors. Three patients in this cohort had a recorded history of at least one prior suicide attempt. ConclusionsMultiple studies have demonstrated increased rates of mental illness in transgender individuals, however, this is the first study to describe the burden of these conditions specifically in the subset of patients who undergo gender affirming laryngeal surgery.

Case Report: Life-Threatening Fluoxetine-Linked Postoperative Bleeding Informed by Pharmacogenetic Evaluation.

Selective serotonin reuptake inhibitors (SSRI) are commonly used for the treatment of depression and anxiety. Inhibition of serotonin reuptake in platelets increases bleeding risk in patients taking SSRIs. Here, we present the case of a 52-year-old patient who developed severe postsurgical bleeding requiring blood transfusion following panniculectomy. SSRI-induced bleeding is dose-related and strongly influenced by individual variations in drug metabolizing enzymes and transporters. Supplementary file1 (MP4 8441 KB).

Evidence for a Role of 5-HT-glutamate Co-releasing Neurons in Acute Stress Mechanisms.

A major subpopulation of midbrain 5-hydroxytryptamine (5-HT) neurons expresses the vesicular glutamate transporter 3 (VGLUT3) and co-releases 5-HT and glutamate, but the function of this co-release is unclear. Given the strong links between 5-HT and uncontrollable stress, we used a combination of c-Fos immunohistochemistry and conditional gene knockout mice to test the hypothesis that glutamate co-releasing 5-HT neurons are activated by stress and involved in stress coping. Acute, uncontrollable swim stress increased c-Fos immunoreactivity in neurons co-expressing VGLUT3 and the 5-HT marker tryptophan hydroxylase 2 (TPH2) in the dorsal raphe nucleus (DRN). This effect was localized in the ventral DRN subregion and prevented by the antidepressant fluoxetine. In contrast, a more controllable stressor, acute social defeat, had no effect on c-Fos immunoreactivity in VGLUT3-TPH2 co-expressing neurons in the DRN. To test whether activation of glutamate co-releasing 5-HT neurons was causally linked to stress coping, mice with a specific deletion of VGLUT3 in 5-HT neurons were exposed to acute swim stress. Compared to wildtype controls, the mutant mice showed increased climbing behavior, a measure of active coping. Wildtype mice also showed increased climbing when administered fluoxetine, revealing an interesting parallel between the behavioral effects of genetic loss of VGLUT3 in 5-HT neurons and 5-HT reuptake inhibition. We conclude that 5-HT-glutamate co-releasing neurons are recruited by exposure to uncontrollable stress. Furthermore, natural variation in the balance of 5-HT and glutamate co-released at the 5-HT synapse may impact stress susceptibility.

A systematic review and critical appraisal of menopause guidelines

Objective and rationaleTo identify and appraise current national and international clinical menopause guidance documents, and to extract and compare the recommendations of the most robust examples.DesignSystematic review.Data sourcesOvid MEDLINE, EMBASE,...

Abstract 117: Bleeding Risks for Acute Ischemic Stroke Patients on Serotonergic Antidepressants and Anticoagulation/Dual Anti-Platelet Therapy

Background: Selective serotonin/serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) are associated with improved stroke recovery. Some clinicians withhold SSRI/SNRIs over bleeding risk concerns. Our objectives were: 1) Quantify the association between early initiation of SSRI/SNRIs and adverse bleeding events among acute ischemic stroke (IS) patients, 2) Determine bleeding risks among patients receiving anticoagulation (AC) or dual antiplatelet therapy (DAPT), and 3) Evaluate bleeding risks between anti-depressant (AD) classes. Methods: Medication naïve first-time IS patients were identified from Electronic Medical Records of 70 healthcare organizations (2003-2023). Patients without ADs were considered “No AD”. Patients started on ADs within 3 months of the indexed stroke were classified as "SSRI/SNRI" or "Other AD" (i.e., Mirtazapine, bupropion, trazodone, or tricyclic ADs). The primary outcome was 1-year risk of major bleeding events (e.g., gastrointestinal/intracranial or shock). Secondary outcomes were hemorrhagic stroke (HS), fall and death. Baseline differences were adjusted for using 1:1 matched propensity scores. Results: A total of n=666,150 patients were included [No AD (n=607,278), SSRI/SNRI (n=35,631), Other AD (n=23,241)]. Early use of SSRI/SNRIs (vs. No ADs) was not associated with an increased risk of a major bleed for all patients (n=35,557 matched pairs) or among patients on AC (n=7,672 matched pairs). However, concurrent use of SSRI/SNRIs and DAPT was associated with a 29% increased risk of HS (RR:1.29, 95% CI: 1.11-1.50, n=8,381 matched pairs). Among patients on ADs, bleed risks were higher for use of “Other ADs” vs. "SSRI/SNRIs" (n=21,810 matched pairs). Discussion: SSRI/SNRIs treat post-stroke depression, promote functional recovery and are generally safe to start during the early stages of recovery for patients with IS. However, an increased risk of HS should be considered when starting ADs among patients on DAPT.

Comprehensive metabolic investigation of dopamine reuptake inhibitor HDMP-28 in equine liver microsomes and Cunninghamella elegans for doping control.

A dopamine reuptake inhibitor is a type of medication or substance that works by blocking the reuptake of dopamine in the brain. Dopamine reuptake inhibitors offer multiple effects, including increased alertness, improved mood, and therapeutic potential for conditions like depression, ADHD, and Parkinson's disease. HDMP-28, or methylnaphthidate, is a potent synthetic stimulant from the phenyltropane class. It surpasses methylphenidate in both dopamine reuptake inhibition and half-life. As a dopamine reuptake inhibitor, it boosts dopamine levels by hindering reuptake into nerve cells, resulting in heightened stimulation and increased energy. In order to comprehensively address both the tangible and potential repercussions of the unauthorized utilization of the aforementioned substance in sports, it is imperative to establish analytical methodologies for the identification of the parent drug and its primary metabolites. Additionally, a comprehensive analysis of the metabolic characteristics of HDMP-28 in both human and animal subjects has yet to be published. This study explores the metabolic conversion of HDMP-28 mediated by equine liver microsomes and Cunninghamella elegans. An extraction and detection method was developed, optimized, and validated for doping assessment in equine urine and plasma. Liquid chromatography-high-resolution mass spectrometry was employed to determine metabolite structures. The study identified 31 (22 phase I and 9 phase II) metabolites of HDMP-28, including hydroxylated, hydrogenated, and hydrolyzed analogs. Glucuronic acid-conjugated metabolites were also detected. This manuscript describes metabolites based on the in vitro studies, which might not be the same in vivo. These findings aid in the detection and understanding of the illicit use of HDMP-28 in equestrian sports.

Control list of high-priority chemicals based on 5-HT-RI functionality and the human health interference effects selective CNN-GRU deep learning model

The antidepressant drug known as 5-HT reuptake inhibitor (5-HT-RI) was commonly detected in biological tissues and result in significant adverse health effects. Homology modeling was used to characterize the functionalities (efficacy and resistance), and the adverse outcome pathway was used to characterize its human health interferences (olfactory toxicity, neurotoxicity, and gut microbial interference). The convolutional neural network coupled with the gated recurrent unit (CNN-GRU) deep learning method was used to construct a comprehensive model of 5-HT-RI functionality and human health interference effects selectivity with small sample data. The architecture with 2 SE, 320 neuronal nodes and 6-folds cross-validation showed the best applicability. The results showed that the confidence interval of the constructed model reached 90 % indicating that the model had reliable prediction ability and generalization ability. Based on the CNN-GRU deep learning model, seven high-priority chemicals with a weak comprehensive effect, including D-VEN, (1R,4S)-SER, S-FLX, CTP, S-CTP, NEF, and VEN, were screened. Based on the molecular three-dimensional structure information, a comprehensive-effect three-dimensional quantitative structure-activity relationship (3D-QSAR) model was constructed to confirm the reliability of the constructed control list of 5-HT-RI high-priority chemicals. Analysis with the ranking of calculated values based on the molecular dynamics method and predicted values based on the CNN-GRU deep learning model, we found that the consistency of the three methods was above 85 %. Additionally, by analyzing the sensitivity, molecular electrostatic potential, polar surface area of the comprehensive-effect CNN-GRU deep learning model, and the electrostatic field of the 3D-QSAR models, we found that the significant effects of five key characteristics (DM, Qyy, Qxz, I, and BP), molecular electronegativity, and polarity significantly affected the high-priority degree of 5-HT-RI. In this study, we provided reasonable and reliable prediction tools and discussed theoretical methods for the risk assessment of functionality and human health interference of emerging pollutants such as 5-HT-RI.

Stereochemical optimization of N,2-substituted cycloalkylamines as norepinephrine reuptake inhibitors.

The norepinephrine transporter (NET), encoded by the SLC6A2 gene, is one of three key monoamine neurotransmitter transporters. Inhibition of NET-mediated reuptake of norepinephrine by monoamine reuptake inhibitors has been the main therapeutic strategy to treat disorders such as depression, ADHD and Parkinson's disease. Nevertheless, lack of efficacy as well as risk of adverse effects are still common for these treatments underscoring the necessity to improve drug discovery efforts for this target. In this study, we developed new inhibitors based on 4-((2-(3,4-dichlorophenyl)cyclopentyl)amino)butan-1-ol (8), a potent NET inhibitor, which emerged from earlier virtual screening efforts using a predictive proteochemometric model. Hence, we optimized the N,2-substituted cycloalkylamine scaffold in three regions to design twenty new derivatives. To establish structure-activity relationships for these NET inhibitors, all novel compounds were tested utilizing an impedance-based 'transporter activity through receptor activation' assay. Moreover, all stereoisomers of the most potent compound (27) were synthesized and evaluated for their inhibitory potencies. Initial screening indicated that modifications in the cyclopentylamine moiety and phenyl substitutions decreased NET inhibition compared to 8, emphasizing the importance of the five-membered ring, secondary amine and dichloro-substitution pattern in NET binding. Substituting the original butylalcohol at the R 2 position with a rigid cyclohexanol yielded lead compound 27, with potency similar to reference inhibitor nisoxetine. Pharmacological characterization of all eight stereoisomers of 27 revealed varying inhibitory potencies, favoring a trans-orientation of the N,2-substituted cyclopentyl moiety. Molecular docking highlighted key interactions and the impact of a hydrophilic region in the binding pocket. This study presents a novel set of moderate to highly potent NET inhibitors, elucidating the influence of molecular orientation in the NET binding pocket and offering valuable insights into drug discovery efforts for monoamine transport-related treatments.

Current treatments of alcohol use disorder.

Emerging treatments for alcohol dependence reveal an intricate interplay of neurobiological, psychological, and circumstantial factors that contribute to Alcohol Use Disorder (AUD). The approved strategies balancing these factors involve extensive manipulations of neurotransmitter systems such as GABA, Glutamate, Dopamine, Serotonin, and Acetylcholine. Innovative developments are engaging mechanisms such as GABA reuptake inhibition and allosteric modulation. Closer scrutiny is placed on the role of Glutamate in chronic alcohol consumption, with treatments like NMDA receptor antagonists and antiglutamatergic medications showing significant promise. Complementing these neurobiological approaches is the progressive shift towards Personalized Medicine. This strategy emphasizes unique genetic, epigenetic and physiological factors, employing pharmacogenomic principles to optimize treatment response. Concurrently, psychological therapies have become an integral part of the treatment landscape, tackling the cognitive-behavioral dimension of addiction. In instances of AUD comorbidity with other psychiatric disorders, Personalized Medicine becomes pivotal, ensuring treatment and prognosis are closely defined by individual characteristics, as exemplified by Lesch Typology models. Given the high global prevalence and wide distribution of AUD, a persistent necessity exists for development and improvement of treatments. Current research efforts are steadily paving paths towards more sophisticated, effective typology-based treatments: a testament to the recognized imperative for enhanced treatment strategies. The potential encapsulated within the ongoing research suggests a promising future where the clinical relevance of current strategies is not just maintained but significantly improved to effectively counter alcohol dependence.

Assessment the effect of Dapoxetine and/or Acetaminophen in rats; neurochemicals and oxidative stress biomarkers evaluation

Dapoxetine is a newer anti‐depressant that is used for severe forms of depression via selective serotonin reuptake inhibition conduit. We aimed to evaluate the effect of different doses of dapoxetine lonely or with acetaminophen (AMP). Seven groups of albino rats were used where dapoxetine was administered orally at the doses of 3, 5, and 8 mg/kg body weight for a period of 14 days in groups 2, 4, and 6, respectively. AMP (67.5 mg/kg body weight) was co‐administered with dapoxetine (3, 5, and 8 mg/kg body weight) for 14 days in groups 3, 5 and 7, respectively. Dapoxetine in mid and high dose plus AMP increased body weight and hematological parameters. Ambulation and rearing were declined with mid and high doses of dapoxetine+AMP, contrary to grooming. Struggling was decreased with high doses of dapoxetine+AMP. High dose of dapoxetine+AMP induced lowering of serotonin and dopamine as well as increasing of cholinesterase. Brain derived neurotrophic factor was decreased in all groups. Oxidative stress biomarkers were augmented with high dose of dapoxetine+AMP. High doses of dapoxetine and/or AMP induced loss of the Purkinje cell layer at cerebellum. The high dose of dapoxetine+AMP denotes behavioral, histopathological and neurochemical alterations, even though no serotonin syndrome occurs.