Receptor Antagonist Activity Research Articles

Vitamin D receptor antagonist activity in wastewater effluents—potential for endocrine disruption

BackgroundEndocrine disrupting chemicals have been identified for a number of human endocrine systems, but there are no reports on vitamin D-antagonistic activities in environmental samples.ObjectivesWe have investigated if there are compounds present in the environment that can act as Vitamin D receptor (VDR) antagonists.MethodsWater samples were collected of the influent and effluent water from five Swedish wastewater treatment facilities and concentrated with solid phase extraction. VDR antagonistic properties of the samples were tested with a cell-based in vitro assay responsive to vitamin D signaling. Cytotoxicity was monitored by three different assays.ResultsWe observed a dose-dependent decrease in the VDR signaling in most studied samples, although the effect was overlapping with cytotoxicity for the influent samples. For effluent samples, we observed clear VDR antagonistic effects also in non-cytotoxic concentrations. The observed effects could not be explained by presence of natural organic matter or cadmium in the water.DiscussionThe vitamin D endocrine system regulates a broad range of physiological processes, and disruption of this system could be associated with serious health consequences. In this study, we report environmental presence of compounds with VDR antagonistic properties, compounds which constitute a new group of potential endocrine disruptors. The VDR antagonism was observed in wastewater treatment facility effluent waters, which are discharged into water systems used as raw water for drinking water production. The findings reported in this study may indicate a potential hazard to human health and aquatic life. Future research is needed to investigate the presence of VDR antagonists in the environment, identification of the causative compounds, and studies of exposure of humans and aquatic organisms to these compounds.

Comparative efficacy and safety of suvorexant and lemborexant for insomnia treatment.

Although suvorexant and lemborexant, which have orexin receptor antagonist activity, are used as sleep medications in Japan, no report has directly compared their efficacy and safety. This study compared the efficacy and safety of the drugs. This retrospective cohort study included patients who presented to the Outpatient Department of Psychiatry at Tottori University Hospital between December 1, 2020, and December 31, 2021. Information was obtained from 108 patients who were newly treated with suvorexant or lemborexant. Data were analyzed after excluding one case of discontinuation due to a post-administration allergic reaction. Improvement in sleep status after administration was assessed retrospectively from medical records by using the Clinical Global Impressions-Improvement (CGI-I) Scale, which is a subscale of the Clinical Global Impressions (CGI) Scale. The incidence of side-effects was obtained from the medical records of the patient's first visit after administration. There was no significant difference between the CGI-I scores in the suvorexant (mean [SD], 3.05 [0.93]) and lemborexant groups (mean [SD], 3.38 [0.83]) (p = 0.10). The incidence of side-effects with continued treatment was not significantly different between the suvorexant group (12.5%) and the lemborexant group (2.9%) (p = 0.10). Patients who switched from suvorexant to lemborexant had CGI-I scores ≤4, and no side-effects were observed after switching to lemborexant. There was no difference in effectiveness between suvorexant and lemborexant. However, lemborexant might cause side-effects less frequently than suvorexant, at least in the early stages of treatment.

Delta Opioid Receptor-Mediated Antidepressant-Like Effects of Diprenorphine in Mice.

Major depressive disorder is a highly common disorder, with a lifetime prevalence in the United States of approximately 21%. Traditional antidepressant treatments are limited by a delayed onset of action and minimal efficacy in some patients. Ketamine is effective and fast-acting, but there are concerns over its abuse liability. Thus, there is a need for safe, fast-acting antidepressant drugs. The opioid buprenorphine shows promise but also has abuse liability due to its mu-agonist component. Preclinical evidence indicates that the delta-opioid system contributes to mood disorders, and delta-opioid agonists are effective in preclinical models of depression- and anxiety-like states. In this study, we test the hypothesis that the mu-opioid antagonist diprenorphine by virtue of its partial delta opioid agonist activity may offer a beneficial profile for an antidepressant medication without abuse liability. Diprenorphine was confirmed to bind with high affinity to all three opioid receptors, and functional experiments for G protein activation verified diprenorphine to be a partial agonist at delta- and kappa-opioid receptors and a mu-antagonist. Studies in C57BL/6 mice demonstrated that an acute dose of diprenorphine produced antidepressant-like effects in the tail suspension test and the novelty-induced hypophagia test that were inhibited in the presence of the delta-selective antagonist, naltrindole. Diprenorphine did not produce convulsions, a side effect of many delta agonists but rather inhibited convulsions caused by the full delta agonist SNC80; however, diprenorphine did potentiate pentylenetetrazole-induced convulsions. Diprenorphine, and compounds with a similar pharmacological profile, may provide efficient and safe rapidly acting antidepressants. SIGNIFICANCE STATEMENT: The management of major depressive disorder, particularly treatment-resistant depression, is a significant unmet medical need. Here we show that the opioid diprenorphine, a compound with mu-opioid receptor antagonist activity and delta- and kappa-opioid receptor partial agonist activities, has rapid onset antidepressant-like activity in animal models. Diprenorphine and compounds with a similar pharmacological profile to diprenorphine should be explored as novel antidepressant drugs.

Identification of Glucocorticoid Receptor Antagonistic Activities and Responsible Compounds in House Dust: Bioaccessibility Should Not Be Ignored.

More and more contaminants in dust have been found to be glucocorticoid receptor (GR) disrupting chemicals. However, little is known about the related potency and responsible toxicants, especially for the main bioaccessible ones in dust. An effect-directed analysis (EDA)-based workflow was developed, including solvent-based exhaustive extraction/tenax-assisted bioaccessible extraction (TBE), high-throughput bioassays, suspect and non-target analysis, as well as in silico candidate selection, for a more realistic identification of responsible contaminants in dust. None of the 39 dust samples from 23 cities in China exhibited GR agonistic activity, while GR antagonistic potencies were detected in 34.8% of samples, being significantly different from the high detection frequency of GR agonistic activities in other environmental media. The GR antagonistic potencies of the dust samples were all reduced after bioaccessible extraction. The mean bioaccessibility of GR antagonistic potency compared with the related exhaustive extracts was 36.8%, and the lowest value was 9%. By using in silico candidate selection, greater than 99% candidate chemical structures which were found by a non-target screening strategy were removed. Di-n-butyl phthalate (DnBP), diisobutyl phthalate (DiBP), and nicotine (NIC) were responsible for the activities of the exhaustive extracts of dust, contributing up to 91% potencies. DiBP and DnBP were also responsible for the bioaccessible activities, contributing up to 79% potencies. However, the contribution from NIC decreased significantly and can be ignored because of its low bioaccessibility. This study suggests that the improved workflow combining extraction, reporter gene bioassays, suspect and non-target analysis, as well as in silico candidate selection is useful for EDA analysis in dust samples. In addition, exhaustive extraction may overestimate the risk of contaminants, while bioaccessibility evaluation based on bioaccessible extraction is essential in both effect evaluation and toxicant identification.

Interactions between heavy metals and sleep duration among pre-and postmenopausal women: A current approach to molecular mechanisms involved

The effects of heavy metals (cadmium, lead, and mercury) and their mixtures on sleep duration in pre-and postmenopausal women, particularly the molecular mechanisms, remain unknown. Here, we assessed the interaction between heavy metals and sleep duration among pre-and postmenopausal women (n = 1134). Furthermore, molecular mechanisms related to sleep disorders induced by studied heavy metals were further analyzed to support the previous findings. We found that serum lead levels were positively related to weekend and weekday sleep duration in premenopausal women. There were interactions between serum lead and mercury and menopausal status for sleep duration. Serum lead and mercury levels were shown to be inversely related to sleep duration in postmenopausal women. Despite the lack of statistically significant associations between mixed heavy metals and sleep duration, there were increasing trends in premenopausal women's sleeping patterns and decreasing trends in postmenopausal women's sleeping patterns. In silico analysis, IL1B, hsa-21-5p, hsa-887-3p, hsa-877-3p, and NR4A1 were identified as the most relevant genes, miRNAs, and transcription factors linked with sleep disorders induced by combined heavy metals (cadmium, lead, and mercury). Furthermore, “type 1 melanocortin receptor binding,” “endocrine hormone secretion,” “interleukin-1 receptor antagonist activity,” “altered melanocortin system,” and “sleep wake disorders” were identified as the predominant molecular mechanisms involved in the pathophysiology of sleep disorders induced by the studied heavy metals. Cut off point values and miRNA sponge templates for heavy metal exposure levels relevant to sleep disorders in pre- and postmenopausal women were reported. Future research is needed to verify our findings and provide insight into the molecular processes of long-term mixed heavy metal exposure in various populations, such as children and the elderly.

The role of AMPA and NMDA receptors in mitragynine effects on hippocampal synaptic plasticity

Mitragynine, an indole alkaloid from the plant Mitragyna speciosa (Kratom), has been reported to modify hippocampal synaptic transmission. However, the role of glutamatergic neurotransmission modulating synaptic plasticity in mitragynine-induced synaptic changes is still unknown. Here, we determined the role of AMPA- and NMDA glutamate receptors in mitragynine-induced synaptic plasticity in the hippocampus. Male Sprague Dawley rats received either vehicle or mitragynine (10 mg/kg), with or without the AMPA receptor antagonist, NBQX (3 mg/kg), or the NMDA receptor antagonist, MK-801 (0.2 mg/kg). Field excitatory postsynaptic potentials (fEPSP) during baseline, paired-pulse facilitation (PPF) and long-term potentiation (LTP) were recorded in-vivo in the hippocampal CA1 area of anaesthetised rats. Basal synaptic transmission and LTP were significantly impaired after mitragynine, NBQX, and MK-801 alone, without an effect on PPF. Combined effects suggest a weak functional AMPA- as well as NMDA receptor antagonist action of mitragynine.

296 (PB076) - Cellular hormone metabolism is critical for canonical androgen receptor antagonist activity

Background: Second-generation androgen receptor (AR) antagonists and an androgen synthesizing enzyme inhibitor have become the standard of care for advanced prostate cancer (PCa). Clinically-approved AR antagonists bind to the AR ligand binding domain (LBD) and competitively inhibit AR function. Dual action AR inhibitors (DAARIs), which bind to the N-terminal domain (NTD) of the AR inhibit AR signaling and lead AR protein degradation, have been identified by our group as potential therapeutics for PCa.

Anti-obesity effects of the dual-active adenosine A2A/A3 receptor-ligand LJ-4378

Background and objectivesA2A adenosine receptor (A2AAR)-mediated signaling in adipose tissues has been investigated as a potential target for obesity-related metabolic diseases. LJ-4378 has been developed as a dual-acting ligand with A2AAR agonist and A3 adenosine receptor (A3AR) antagonist activity. The current study aimed to investigate the anti-obesity effects of LJ-4378 and its underlying molecular mechanisms.MethodsImmortalized brown adipocytes were used for in vitro analysis. A high-fat diet (HFD)-induced obesity and cell death-inducing DFFA-like effector A reporter mouse models were used for in vivo experiments. The effects of LJ-4378 on lipolysis and mitochondrial metabolism were evaluated using immunoblotting, mitochondrial staining, and oxygen consumption rate analyses. The in vivo anti-obesity effects of LJ-4378 were evaluated using indirect calorimetry, body composition analyses, glucose tolerance tests, and histochemical analyses.ResultsIn vitro LJ-4378 treatment increased the levels of brown adipocyte markers and mitochondrial proteins, including uncoupling protein 1. The effects of LJ-4378 on lipolysis of adipocytes were more potent than those of the A2AAR agonist or A3AR antagonist. In vivo, LJ-4378 treatment increased energy expenditure by 17.0% (P value < 0.0001) compared to vehicle controls. LJ-4378 (1 mg/kg, i.p.) treatment for 10 days reduced body weight and fat content by 8.24% (P value < 0.0001) and 24.2% (P value = 0.0044), respectively, and improved glucose tolerance in the HFD-fed mice. LJ-4378 increased the expression levels of brown adipocyte markers and mitochondrial proteins in interscapular brown and inguinal white adipose tissue.ConclusionThese findings support the in vivo anti-obesity effects of LJ-4378, and suggest a novel therapeutic approach to combat obesity and related metabolic diseases.

Synthesis of Hydantoin Androgen Receptor Antagonists and Study on Their Antagonistic Activity.

Hydroxymethylthiohydantoin, hydroxymethylthiohydantoin, and hydantoin, containing a pyridine group, were synthesized to study their androgen receptor antagonistic activities. Among them, compounds 6a/6c/7g/19a/19b exhibited excellent androgen receptor antagonistic activity, which was consistent with or even superior to enzalutamide. In addition, compounds 19a and 19b exhibited better antiproliferative activity than enzalutamide in prostate cancer cells. The results show that compound 19a has great potential as a new AR antagonist.

Hazardous chemicals in non-polar extracts from paper and cardboard food packaging: an effect-based evaluation

BackgroundFood contact articles are used in our everyday life and information regarding the potential health hazards of migrating chemicals for humans is scarce. In this study, an effect-based evaluation of non-polar extracts of food contact articles made of paper and board was conducted with a panel of eight bioassay endpoints. These, health-relevant endpoints, included oxidative stress, inflammation, genotoxicity, xenobiotic metabolism and hormone receptor effects.ResultsIn total, 62 food contact articles were pooled into 19 groups, in which articles intended to be used for similar types of food item(s) were pooled, and extracted with acetone:n-hexane (1:4). These were then tested in the effect-based bioassays. Bioactivities were detected for multiple materials in six out of eight assays, the two assays showing no effects were NFκB and androgen receptor agonistic response. In essence, the detection rates of the tested non-polar extracts were 72% for antagonistic effects on the estrogen receptor, 72% for antagonistic effects on the androgen receptor, 47% for oxidative stress, 28% for agonistic effects on the estrogen receptor and 33% for genotoxicity. The bioequivalent concentrations ranges in extracts of 10 mg food contact article/mL cell culture media were: for oxidative stress from 2.45 to 5.64 µM tBHQ equivalents, estrogen receptor agonistic activity from 1.66 to 6.33 ρM estradiol equivalents, estrogen receptor antagonistic activity from 1.21 × 10–3 to 4.20 × 10–3 μM raloxifene equivalents and androgen antagonistic activity 0.08–0.46 μM hydroxyflutamide equivalents. The extracts that were bioactive in multiple assays were: baking moulds, boxes for popcorn, infant formula/skimmed milk, porridge/flour mixes, pizza, fries’ and hamburgers as well as packages for frozen food.ConclusionNon-polar extracts of food contact articles contain compounds that can activate molecular initiating events in toxicity pathways of high relevance to human health. These events included endocrine-disruptive activities, oxidative stress and genotoxicity. Effect-based methods proved to be a valuable tool for evaluating food package articles, as they can detect potentially hazardous effects of both known and unknown chemicals as well as potential cocktail effects.

Pentadecanoylcarnitine is a newly discovered endocannabinoid with pleiotropic activities relevant to supporting physical and mental health

As an emerging dietary essential fatty acid, pentadecanoic acid (C15:0) is expected to have bioactive metabolites with broad health benefits. Here, we evaluated pentadecanoylcarnitine, an endogenous C15:0 metabolite, for dose dependent cell-based activities, including measurement of its effects on 148 clinically relevant biomarkers across twelve primary human cell systems mimicking various disease states. Mechanisms of action for pentadecanoylcarnitine were also assessed across 78 cell-based target assays. Pentadecanoylcarnitine had dose-dependent anti-inflammatory activities, including lower IL-1α, ITAC, MCP-1, and IP-10, across five cell systems relevant to treating cardiovascular, immune, neoplastic, pulmonary, and skin diseases. Targeted assays showed pentadecanoylcarnitine as a full-acting cannabinoid 1 and 2 receptor agonist (EC50 3.7 and 3.2 µM, 111% and 106% maximum activity compared to the positive control, respectively). Pentadecanoylcarnitine also had 5-HT1A and 5-HT1B receptor agonist and histamine H1 and H2 receptor antagonist activities. In summary, pentadecanoylcarnitine, a second discovered full-acting endocannabinoid, had broad pleiotropic activities relevant to regulating inflammation, pain, mood, and sleep. This study’s findings further the need to evaluate the potential health impacts of C15:0 nutritional deficiencies caused by population-wide avoidance of all dietary saturated fats, including C15:0.

Medicinal herbs in treating chemotherapy-induced nausea and vomiting: A review.

Cancer development entangles with mutation and selection for cells that progressively increase capacity for proliferation and metastasis at the cellular level. Surgery, chemotherapy, and radiotherapy are the standard treatments to manage several types of cancer. Chemotherapy is toxic for both normal and cancer cells and can induce unfavorable conditions, such as chemotherapy-induced nausea and vomiting (CINV), that reduce patients' quality of life. Emesis after chemotherapy is categorized into two classes acute and delayed. Since ancient times, herbal medicines have been used in various cultures to manage stomachache, vomiting, and nausea. In this manuscript, the antiemetic mechanisms of several herbal medicines and their preparations such as Zingiber officinale (5-HT, NK-1 receptor and muscarinic antagonist activity), Mentha spicata (5-HT antagonist activity), Scutellaria baicalensis (antioxidant activity), Persumac (useful in delayed phase through antioxidant, anti-inflammatory, and anti-contractile properties) and Rikkunshito (supportive in acute and delayed phase through 5-HT receptor antagonist activity) have been reviewed to show their potential effects on decreasing CINV and attract scientists attention to formulate more herbal medicine to alleviate CINV in cancer patients. However, it is crucial to say that additional high-quality investigations are required to firmly verify the clinical effectiveness and safety of each plant/compound.

Discovery of novel orexin receptor antagonists using a 1,3,5-trioxazatriquinane bearing multiple effective residues (TriMER) library

Structurally diverse small compounds are utilized to obtain hit compounds that have suitable pharmacophores in appropriate three-dimensional conformations for the target drug receptors. We have focused on the 1,3,5-trioxazatriquinane skeleton, which has a rigid bowl-like structure enabling the diverse orientation of side chain units, leading to a novel small-scale focused library based on the skeleton. In the library screening for the orexin receptor, some of the compounds showed orexin receptor antagonistic activity with a high hit rate of 7%. By optimizing the hit compounds, we discovered a potent dual orexin receptor antagonist, 38b, and a selective orexin 1 receptor antagonist, 41b carrying the same plane structure. Both compounds showed reasonable brain permeability and beneficial effects when administered intraperitoneally to wild-type mice. Docking simulations of their eutomers, (−)-38b and (+)-41b, with orexin receptors suggested that the interaction between the 1,3,5-trioxazatriquinane core structure and the hydrophobic subpocket in orexin receptors enables a U-shape structure, which causes tight van der Waals interactions with the receptors similar to SB-334867, a selective orexin 1 receptor antagonist. These results indicate that the library approach utilizing the 1,3,5-trioxazatriquinanes bearing multiple effective residues (TriMERs) might be useful for the hit discovery process targeting not only opioid and orexin receptors but other G-protein coupled receptors.

Insights of Valacyclovir in Treatment of Alzheimer's Disease: Computational Docking Studies and Scopolamine Rat Model.

Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity. This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease. Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested. Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus. Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.

IGF-1 release in the medial prefrontal cortex mediates the rapid and sustained antidepressant-like actions of ketamine

Ketamine, an N-methyl-D-aspartate receptor antagonist, exerts rapid and sustained antidepressant actions. Preclinical studies demonstrated that the release of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor in the medial prefrontal cortex (mPFC) is essential for the antidepressant-like effects of ketamine. However, the role of other neurotrophic factors in the antidepressant-like effects of ketamine has not been fully investigated. Since the intra-mPFC infusion of insulin-like growth factor 1 (IGF-1) reportedly produced antidepressant-like effects, the present study examined the role of endogenous intra-mPFC IGF-1 signaling in the antidepressant-like actions of ketamine. In vivo microdialysis showed that ketamine (10 and 30 mg/kg) significantly increased extracellular IGF-1 levels in the mPFC of male C57BL/6J mice for at least 5 h. Infusion of an IGF-1 neutralizing antibody (nAb; 160 ng/side) into the mPFC 15 min before or 2 h after ketamine injection blocked the antidepressant-like effects of ketamine in three different behavioral paradigms (forced swim, female urine sniffing, and novelty-suppressed feeding tests were conducted 1, 3 and 4 days post-ketamine, respectively). The ketamine-like antidepressant-like actions of the intra-mPFC infusion of BDNF (100 ng/side) and IGF-1 (50 ng/side) respectively were not blocked by co-infused IGF-1 nAb and BDNF nAb (200 ng/side). Moreover, intra-mPFC infusion of IGF-1 nAb 2 h post-ketamine blocked the antidepressant-like effects of ketamine in a murine lipopolysaccharide (LPS)-induced depression model. Intra-mPFC IGF-1 infusion also produced antidepressant-like effects in the LPS-challenged mice via mechanistic target of rapamycin complex 1 activation. These results suggest that persistent release of IGF-1, independently of BDNF, in the mPFC is essential for the antidepressant-like actions of ketamine.

Stereospecific lasofoxifene derivatives reveal the interplay between estrogen receptor alpha stability and antagonistic activity in ESR1 mutant breast cancer cells.

Chemical manipulation of estrogen receptor alpha ligand binding domain structural mobility tunes receptor lifetime and influences breast cancer therapeutic activities. Selective estrogen receptor modulators (SERMs) extend estrogen receptor alpha (ERα) cellular lifetime/accumulation. They are antagonists in the breast but agonists in the uterine epithelium and/or in bone. Selective estrogen receptor degraders/downregulators (SERDs) reduce ERα cellular lifetime/accumulation and are pure antagonists. Activating somatic ESR1 mutations Y537S and D538G enable resistance to first-line endocrine therapies. SERDs have shown significant activities in ESR1 mutant setting while few SERMs have been studied. To understand whether chemical manipulation of ERα cellular lifetime and accumulation influences antagonistic activity, we studied a series of methylpyrollidine lasofoxifene (Laso) derivatives that maintained the drug's antagonistic activities while uniquely tuning ERα cellular accumulation. These molecules were examined alongside a panel of antiestrogens in live cell assays of ERα cellular accumulation, lifetime, SUMOylation, and transcriptional antagonism. High-resolution x-ray crystal structures of WT and Y537S ERα ligand binding domain in complex with the methylated Laso derivatives or representative SERMs and SERDs show that molecules that favor a highly buried helix 12 antagonist conformation achieve the greatest transcriptional suppression activities in breast cancer cells harboring WT/Y537S ESR1. Together these results show that chemical reduction of ERα cellular lifetime is not necessarily the most crucial parameter for transcriptional antagonism in ESR1 mutated breast cancer cells. Importantly, our studies show how small chemical differences within a scaffold series can provide compounds with similar antagonistic activities, but with greatly different effects of the cellular lifetime of the ERα, which is crucial for achieving desired SERM or SERD profiles.

An analog of [d-Trp]CJ-15,208 exhibits kappa opioid receptor antagonism following oral administration and prevents stress-induced reinstatement of extinguished morphine conditioned place preference

Opioid use disorder (OUD) relapse rates are discouragingly high, underscoring the need for new treatment options. The macrocyclic tetrapeptide natural product CJ-15,208 and its stereoisomer [d-Trp]CJ-15,208 demonstrate kappa opioid receptor (KOR) antagonist activity upon oral administration which prevents stress-induced reinstatement of cocaine-seeking behavior. In order to further explore the structure-activity relationships and expand the potential therapeutic applications of KOR antagonism for the treatment of OUD, we screened a series of 24 analogs of [d-Trp]CJ-15,208 with the goal of enhancing KOR antagonist activity. From this screening, analog 22 arose as a compound of interest, demonstrating dose-dependent KOR antagonism after central and oral administration lasting at least 2.5 h. In further oral testing, analog 22 lacked respiratory, locomotor, or reinforcing effects, consistent with the absence of opioid agonism. Pretreatment with analog 22 (30 mg/kg, p.o.) prevented stress-induced reinstatement of extinguished morphine conditioned place preference and reduced some signs of naloxone-precipitated withdrawal in mice physically dependent on morphine. Collectively, these data support the therapeutic potential of KOR antagonists to support abstinence in OUD and ameliorate opioid withdrawal.

Ficus religiosa: A beneficial medicinal plant

In India, herbs have been the primary means of treatment. The existence of secondary plant metabolites, which are combinations of chemical substances with different amalgams, in one or more sections of medicinal plants confers therapeutic qualities. Ficus religiosa, sometimes known as peepal, belongs to the Moraceae family of plants. The Bo tree, Ficus religiosa, provided shelter to the Buddha as he divined the "Truths." In Ficus religiosa, phenolic components, hydrocarbons, aliphatic alcohols, volatile components, phytosterols, amino acids, furanocoumarins, and a few more types of secondary metabolites have been isolated by phytochemical studies. Both (In vitro and in vivo) pharmacological activities of Ficus religiosa crude extracts and isolated components included anti-inflammatory, analgesic, antimicrobial, antiviral, hypolipidemic, antioxidant, immunomodulatory, antiasthmatic, parasympathetic modulator, estrogenic, anticancer, antiulcer, antianxiety, anthelmintic, endothelial receptor antagonistic, apoptosis inducer, and hypotensive activities.&#x0D; Keywords: Ficus religiosa, phytoconstituents, pharmacology, toxicity

Tamoxifen Twists Again: On and Off-Targets in Macrophages and Infections.

Beyond the wide use of tamoxifen in breast cancer chemotherapy due to its estrogen receptor antagonist activity, this drug is being assayed in repurposing strategies against a number of microbial infections. We conducted a literature search on the evidence related with tamoxifen activity in macrophages, since these immune cells participate as a first line-defense against pathogen invasion. Consistent data indicate the existence of estrogen receptor-independent targets of tamoxifen in macrophages that include lipid mediators and signaling pathways, such as NRF2 and caspase-1, which allow these cells to undergo phenotypic adaptation and potentiate the inflammatory response, without the induction of cell death. Thus, these lines of evidence suggest that the widespread antimicrobial activity of this drug can be ascribed, at least in part, to the potentiation of the host innate immunity. This widens our understanding of the pharmacological activity of tamoxifen with relevant therapeutic implications for infections and other clinical indications that may benefit from the immunomodulatory effects of this drug.

Total Synthesis and Biosynthesis of Cyclodepsipeptide CochinmicinI.

Phenylglycines are building blocks of many non-ribosomally synthesized peptides. The dihydroxyphenylglycine-containing cyclodepsipeptide cochinmicin I exhibits endothelin receptor antagonist activity. Therefore, it represents an interesting and synthetically challenging molecule because of the racemization-prone nature of dihydroxyphenylglycine. We present the total synthesis of cochinmicin I and the non-natural derivative cochinmicin VI and describe the identification and assignment of the cochinmicin (cmn) biosynthesis gene cluster, encoding a five-module non-ribosomal peptide synthetase for cochinmicin assembly.