Weak Antagonist Research Articles

Unexpected Course of Reaction Between (1E,3E)-1,4-Dinitro-1,3-butadiene and N-Methyl Azomethine Ylide-A Comprehensive Experimental and Quantum-Chemical Study.

In recent times, interest in the chemistry of conjugated nitrodienes is still significantly increasing. In particular, the application of these compounds as building blocks to obtain heterocycles is a popular object of research. Therefore, in continuation of our research devoted to the topic of conjugated nitrodienes, experimental and quantum-chemical studies of a cycloaddition reaction between (1E,3E)-1,4-dinitro-1,3-butadiene and N-methyl azomethine ylide have been investigated. The computational results present that the tested reaction is realized through a pdr-type polar mechanism. In turn, the experimental study shows that in a course of this cycloaddition, only one reaction product in the form of 1-methyl-3-(trans-2-nitrovinyl)-Δ3-pyrroline is created. The constitution of this compound has been confirmed via spectroscopic methods. Finally, ADME analysis indicated that the synthesized Δ3-pyrroline exhibits biological potential, and it is a good drug candidate according to Lipinski, Veber and Egan rules. Nevertheless, PASS simulation showed that the compound exhibits weak antimicrobial, inhibitory and antagonist properties. Preliminary in silico research shows that although the obtained Δ3-pyrroline is not a good candidate for a drug, the presence of a nitrovinyl moiety in its structure indicates that the compound is an initial basis for further modifications.

Molecular Targets of Minor Cannabinoids in Breast Cancer: In Silico and In Vitro Studies.

Breast cancer therapy has been facing remarkable changes. Classic treatments are now combined with other therapies to improve efficacy and surpass resistance. Indeed, the emergence of resistance demands the development of novel therapeutic approaches. Due to key estrogen signaling, estrogen receptor-positive (ER+) breast cancer treatment has always been focused on aromatase inhibition and ER modulation. Lately, the effects of phytocannabinoids, mainly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), have been evaluated in different cancers, including breast. However, Cannabis sativa contains more than 120 phytocannabinoids less researched and understood. Here, we evaluated, both in silico and in vitro, the ability of 129 phytocannabinoids to modulate important molecular targets in ER+ breast cancer: aromatase, ER, and androgen receptor (AR). In silico results suggested that some cannabinoids may inhibit aromatase and act as ERα antagonists. Nine selected cannabinoids showed, in vitro, potential to act either as ER antagonists with inverse agonist properties, or as ER agonists. Moreover, these cannabinoids were considered as weak aromatase inhibitors and AR antagonists with inverse agonist action. Overall, we present, for the first time, a comprehensive analysis of the actions of the phytocannabinoids in targets of ER+ breast tumors, pointing out their therapeutic potential in cancer and in other diseases.

Genus-wide analysis of Trichoderma antagonism toward Pythium and Globisporangium plant pathogens and the contribution of cellulases to the antagonism.

Parasitism is an important lifestyle in the Trichoderma genus but has not been studied in a genus-wide way toward Pythium and Globisporangium hosts. Our approach screened a genus-wide set of 30 Trichoderma species in dual culture assays with two soil-borne Pythium and three Globisporangium plant-parasitic species and used exo-proteomic analyses, with the aim to correlate Trichoderma antagonism with potential strategies for attacking Pythium and Globisporangium. The Trichoderma spp. showed a wide range of antagonism from strong to weak, but the same Trichoderma strain showed similar levels toward all the Pythium and Globisporangium species. The Trichoderma enzymes from strong (Trichoderma asperellum, Trichoderma atroviride, and Trichoderma virens), moderate (Trichoderma cf. guizhouense and Trichoderma reesei), and weak (Trichoderma parepimyces) antagonists were induced by the autoclaved mycelia of one of the screened Pythium species, Pythium myriotylum. The variable proportions of putative cellulases, proteases, and redox enzymes suggested diverse as well as shared strategies amongst the antagonists. There was a partial positive correlation between antagonism from microscopy and the cellulase activity induced by autoclaved P. myriotylum mycelia in different Trichoderma species. The deletion of the cellulase transcriptional activator XYR1 in T. reesei led to lower antagonism toward Pythium and Globisporangium. The antagonism of Pythium and Globisporangium appears to be a generic property of Trichoderma as most of the Trichoderma species were at least moderately antagonistic. While a role for cellulases in the antagonism was uncovered, cellulases did not appear to make a major contribution to T. reesei antagonism, and other factors are also likely contributing.IMPORTANCETrichoderma is an important genus widely distributed in nature with broad ecological impacts and applications in the biocontrol of plant diseases. The Pythium and Globisporangium genera of fungus-like water molds include many important soil-borne plant pathogens that cause various diseases. Most of the Trichoderma species showed at least a moderate ability to compete with or antagonize the Pythium and Globisporangium hosts, and microscopy showed examples of parasitism (a slow type of killing) and predation (a fast type of killing). Hydrolytic enzymes such as cellulases and proteases produced by Trichoderma likely contribute to the antagonism. A mutant deficient in cellulase activity had reduced antagonism. Interestingly, Pythium and Globisporangium species contain cellulose in their cell walls (unlike true fungi such as Trichoderma), and the cellulolytic ability of Trichoderma appears beneficial for antagonism of water molds.

Functional Activity of Enantiomeric Oximes and Diastereomeric Amines and Cyano Substituents at C9 in 3-Hydroxy-N-phenethyl-5-phenylmorphans.

The synthesis of stereochemically pure oximes, amines, saturated and unsaturated cyanomethyl compounds, and methylaminomethyl compounds at the C9 position in 3-hydroxy-N-phenethyl-5-phenylmorphans provided μ-opioid receptor (MOR) agonists with varied efficacy and potency. One of the most interesting compounds, (2-((1S,5R,9R)-5-(3-hydroxyphenyl)-2-phenethyl-2-azabicyclo[3.3.1]nonan-9-yl)acetonitrile), was found to be a potent partial MOR agonist (EC50 = 2.5 nM, %Emax = 89.6%), as determined in the forskolin-induced cAMP accumulation assay. Others ranged in potency and efficacy at the MOR, from nanomolar potency with a C9 cyanomethyl compound (EC50 = 0.85 nM) to its totally inactive diastereomer, and three compounds exhibited weak MOR antagonist activity (the primary amine 3, the secondary amine 8, and the cyanomethyl compound 41). Many of the compounds were fully efficacious; their efficacy and potency were affected by both the stereochemistry of the molecule and the specific C9 substituent. Most of the MOR agonists were selective in their receptor interactions, and only a few had δ-opioid receptor (DOR) or κ-opioid receptor (KOR) agonist activity. Only one compound, a C9-methylaminomethyl-substituted phenylmorphan, was moderately potent and fully efficacious as a KOR agonist (KOR EC50 = 18 nM (% Emax = 103%)).

Effect of temperature-humidity index on the evolution of trade-offs between fertility and production in dairy cattle

BackgroundIn the current context of climate change, livestock production faces many challenges to improve the sustainability of systems. Dairy farming, in particular, must find ways to select animals that will be able to achieve sufficient overall production while maintaining their reproductive ability in environments with increasing temperatures. With future forecasted climate conditions in mind, this study used data from Holstein and Montbeliarde dairy cattle to: (1) estimate the genetic-by-temperature-humidity index (THI) interactions for female fertility, and (2) evaluate the production-fertility trade-off with increasing values of THI.ResultsTwo-trait random regression models were fitted for conception rate (fertility) and test-day protein yield (production). For fertility, genetic correlations between different THI values were generally above 0.75, suggesting weak genotype-by-THI interactions for conception rate in both breeds. However, the genetic correlations between the conception rate breeding values at the current average THI (THI = 50, corresponding to a 24-h average temperature of 8 °C at 50% relative humidity) and their slopes (i.e., potential reranking) for heat stress scenarios (THI > 70), were different for each breed. For Montbeliarde, this correlation tended to be positive (i.e., overall the best reproducers are less affected by heat stress), whereas for Holstein it was approximately zero. Finally, our results indicated a weak antagonism between production and fertility, although for Montbeliarde this antagonism intensified with increasing THI.ConclusionsWithin the range of weather conditions studied, increasing temperatures are not expected to exacerbate the fertility-production trade-off. However, our results indicated that the animals with the best breeding values for production today will be the most affected by temperature increases, both in terms of fertility and production. Nonetheless, these animals should remain among the most productive ones during heat waves. For Montbeliarde, the current selection program for fertility seems to be adequate for ensuring the adaptation of fertility traits to temperature increases, without adverse effects on production. Such a conclusion cannot be drawn for Holstein. In the future, the incorporation of a heat tolerance index into dairy cattle breeding programs would be valuable to promote the selection of animals adapted to future climate conditions.

Small-molecule positive allosteric modulation of homomeric kainate receptors GluK1-3: development of screening assays and insight into GluK3 structure.

The kainate receptors GluK1-3 (glutamate receptor ionotropic, kainate receptors 1-3) belong to the family of ionotropic glutamate receptors and are essential for fast excitatory neurotransmission in the brain, and are associated with neurological and psychiatric diseases. How these receptors can be modulated by small-molecule agents is not well understood, especially for GluK3. We show that the positive allosteric modulator BPAM344 can be used to establish robust calcium-sensitive fluorescence-based assays to test agonists, antagonists, and positive allosteric modulators of GluK1-3. The half-maximal effective concentration (EC50) of BPAM344 for potentiating the response of 100 μm kainate was determined to be 26.3 μm for GluK1, 75.4 μm for GluK2, and 639 μm for GluK3. Domoate was found to be a potent agonist for GluK1 and GluK2, with an EC50 of 0.77 and 1.33 μm, respectively, upon co-application of 150 μm BPAM344. At GluK3, domoate acts as a very weak agonist or antagonist with a half-maximal inhibitory concentration (IC50) of 14.5 μm, in presence of 500 μm BPAM344 and 100 μm kainate for competition binding. Using H523A-mutated GluK3, we determined the first dimeric structure of the ligand-binding domain by X-ray crystallography, allowing location of BPAM344, as well as zinc-, sodium-, and chloride-ion binding sites at the dimer interface. Molecular dynamics simulations support the stability of the ion sites as well as the involvement of Asp761, Asp790, and Glu797 in the binding of zinc ions. Using electron microscopy, we show that, in presence of glutamate and BPAM344, full-length GluK3 adopts a dimer-of-dimers arrangement.

Metabolic Features of a Novel Trichoderma asperellum YNQJ1002 with Potent Antagonistic Activity against Fusarium graminearum.

Trichoderma, a well-known and extensively studied fungal genus, has gained significant attention for its remarkable antagonistic abilities against a wide range of plant pathogens. In this study, a total of 108 Trichoderma isolates were screened through in vitro dual antagonistic assays and culture filtrate inhibition against Fusarium graminearum. Of these, the YNQJ1002 displayed noteworthy inhibitory activities along with thermal stability. To validate the metabolic differences between YNQJ1002 and GZLX3001 (with strong and weak antagonism, respectively), UPLC-TOF-MS/MS mass spectrometry was employed to analyze and compare the metabolite profiles. We identified 12 significantly up-regulated metabolites in YNQJ1002, which include compounds like Trigoneoside, Torvoside, trans,trans-hepta-2,4,6-trienoic acid, and Chamazulene. These metabolites are known for their antimicrobial properties or signaling roles as components of cell membranes. Enriched KEGG analysis revealed a significant enrichment in sphingolipid metabolism and linoleic acid metabolism, as well as autophagy. The results demonstrated that YNQJ1002's abundance of antimicrobial substances, resulting from specific metabolic pathways, enhanced its superior antagonistic activity against F. graminearum. Finally, YNQJ1002 was identified using the ITS, tef1-1α, and rpb2 regions, with MIST system sequence matching confirming its classification within the species. Overall, we have obtained a novel strain, T. asperellum YNQJ1002, which is rich in metabolites and shows potential antagonistic activity against F. graminearum. This study has opened promising prospects for the development of innovative Trichoderma-derived antifungal compounds, featuring a unique mechanism against pathogens.

Relaxin family peptide receptors in GtoPdb v.2023.1

Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [23, 119]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [260]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [259]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [267] and RXFP2 [132] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [262]. INSL5 and relaxin-3 interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [321, 152].

Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies.

Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold-the PPAR agonists (1a (αEC50 1.0 μM) and 1b (γEC50 0.012 μM)) and antagonists (2a (αIC50 6.5 μM) and 2b (αIC50 0.98 μM, with a weak antagonist activity on γ isoform))-on proinflammatory and oxidative stress biomarkers. The PPAR ligands 1a-b and 2a-b (0.1-10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E2, and 8-iso-PGF2α were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE2, and 8-iso-PGF2α levels after 1a treatment. On the other hand, 1b decreased LPS-induced LDH activity. Compared to the control, 1a stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, 1b increased UCP1, DIO2, and PPARγ gene expression. 2a-b caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, 2a-b significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after 2b treatment. The novel PPARα agonist 1a might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist 1b could play a minor role in the regulation of inflammatory pathways.

Preparation of Superactive Prolactin Receptor Antagonists.

Most breast cancer deaths are caused by malignant estrogen receptor-positive breast tumors that later recur as metastatic disease. Prolactin (PRL) has been documented as a factor promoting breast cancer development and metastasis. We therefore developed superactive prolactin receptor (PRLR) antagonists aimed at blocking PRL action. We purified 12 novel mutants to homogeneity as monomers, and the most potent antagonist was over 95-fold more active than the previously reported weak antagonist, the mutant Del 1-9 human PRL G129R. This enhanced antagonistic activity resulted mostly from prolonged interaction with the extracellular domain (ECD) of PRLR. All mutants were properly refolded, as indicated by interaction with human PRLR-ECD and by circular dichroism analysis. We then prepared monopegylated variants of the most active mutants to extend their biological half-life in vivo.

Historical Pathways for Opioid Addiction, Withdrawal with Traditional and Alternative Treatment Options with Ketamine, Cannabinoids, and Noribogaine: A Narrative Review.

Even as prescription opioid dispensing rates have begun to decrease, the use of illicit opioids such as heroin and fentanyl has increased. Thus, the end of the opioid epidemic is not in sight, and treating patients that are addicted to opioids remains of utmost importance. Currently, the primary pharmacotherapies used to treat opioid addiction over the long term are the opioid antagonist naltrexone, the partial-agonist buprenorphine, and the full agonist methadone. Naloxone is an antagonist used to rapidly reverse opioid overdose. While these treatments are well-established and used regularly, the gravity of the opioid epidemic necessitates that all possible avenues of treatment be explored. Therefore, in this narrative review, we analyze current literature regarding use of the alternative medications ketamine, noribogaine, and cannabinoids in treating patients suffering from opioid use disorder. Beyond its use as an anesthetic, ketamine has been shown to have many applications in several medical specialties. Of particular interest to the subject at hand, ketamine is promising in treating individuals addicted to opioids, alcohol, and cocaine. Therapeutically administered cannabinoids have been proposed for the treatment of multiple illnesses. These include, but are not limited to epilepsy, Parkinson's disease, multiple sclerosis, chronic pain conditions, anxiety disorders, and addiction. The cannabinoid dronabinol has been seen to have varying effects. High doses appear to reduce withdrawal symptoms but this comes at the expense of increased adverse side effects such as sedation and tachycardia. Noribogaine is a weak MOR antagonist and relatively potent KOR agonist, which may explain the clinical anti-addictive effects. More research should be done to assess the viability of these medications for the treatment of OUD and withdrawal.

Pharmacological characterization of kratom alkaloids at opiate receptors: binding affinities, in vitro and in vivo functional assessments

Kratom (Mitragyna speciosa) is consumed by 10‐15 million individuals in the US for its mood‐elevating effects, as an alternative to traditional opiates for pain relief and to attenuate opiate withdrawal symptoms. Complex natural products, such as kratom, contain a variety of chemicals whose combined effects can only be understood by the meticulous identification and characterization of the individual chemicals and their effects in preclinical model systems. Twenty‐five indole and oxindole kratom alkaloids were evaluated for mu (MOR), delta (DOR) and kappa (KOR) opiate receptors binding affinities, opiate receptor mediated G‐protein activation, inhibition of forskolin stimulated cAMP accumulation and b‐arrestin2 recruitment. Several indole and oxindole alkaloids exhibited partial agonism at the MOR (7‐hydroxymitragynine, corynoxine A > epiallo‐isopaynantheine, isospeciofoline, speciociliatine, corynoxine B > mitragynine, 3‐epicorynoxine B > paynantheine and speciogynine) – all of which also exhibited strong G protein bias. Mitraciliatine and isopaynantheine were weak MOR antagonists. Speciophylline exhibited positive allosteric modulatory activity at the MOR as evidenced by increased affinity of DAMGO binding and potentiation of [met]‐enkephalin‐induced inhibition of forskolin stimulated cAMP activity in the absence of intrinsic activity. Corynoxine A induced displayed similar affinity at the mu opiate receptor as 7 hydroxymitragynine but was less potent in the nociceptive hot plate assay and the mechanical allodynia von Frey test. Corynoxine did not significantly alter respiration or heart rate or induce a conditioned place preference. Results demonstrate the pharmacological complexity of kratom alkaloids and have important implications for determining the combined effects of less abundant indole and oxindole alkaloids with regard to the therapeutic as well as potential harmful effects of kratom.

Low‐Dose 6β‐Naltrexol Prevents Opioid Dependence Without Affecting Antinociception

We asked whether opioid dependence can be prevented during opioid pain therapy or maintenance therapy of opioid use disorder. We hypothesize that 6β‐naltrexol (6BN) binds to the basally activated μ opioid receptor (MOR) prevalent in dependence and gradually reverts it to its resting state, proposing a novel MOR model (1). Clinical utility of opioid analgesics is compromised by adverse effects and addiction liability, largely mediated by MOR, which displays spontaneous basal activity. It’s upregulation by opioid agonists can contribute to opioid dependence. Acting as inverse MOR antagonists in the dependent state, naltrexone and naloxone cause withdrawal at exceedingly low doses. We had identified 6β‐naltrexol (6BN) as a neutral MOR antagonist, which blocks antinociception and causes withdrawal only at much higher doses, even though its MOR affinity equals that of naltrexone. Weak antagonist potency of 6BN is due to both its neutral antagonism and peripheral selectivity because of slow entry into the brain. Nevertheless, low‐dose 6BN (LD‐6BN; <0.1 mg/kg) potently prevents the development of dependence in adult guinea pigs treated with methadone (6BN IC50=~0.01 mg/kg), presumably a central effect (2). To test whether LD‐6BN establishes meaningful 6BN levels in the brain, we measure blood and brain levels with a highly sensitive mass spectrometry assay. Following an s.c. 6BN dose of 0.02 mg/kg in guinea pigs, blood levels initially exceed brain levels tenfold, consistent with its peripheral selectivity, followed by rapid elimination from blood (t1/2 ~1h). In contrast, 6BN levels increased over 2h and persisted in brain for 8h at 1‐2 nM levels (t1/2 ~5h). Co‐administration of a saturating naloxone dose reduced 6BN brain levels by ~70% at 1‐3h, indicating saturable high affinity binding. The results show that LD‐6BN reaches central opioid receptor sites by slow penetration and long retention in the brain, enabling a possible gradually reversal of upregulated basal MOR activity. LD‐6BN appears to act as a dependence modulator rather than a typical opioid antagonist, accounting for its prevention of opioid dependence during agonist treatment, and possibly other aspects of opioid addiction.1. W. Sadee, J. Oberdick, Z. Wang. Biased Opioid Antagonists as Modulators of Opioid Dependence: Opportunities to Improve Pain Therapy and Opioid Use Management. Molecules 25, 4163; doi:10.3390/molecules25184163 (2020)2. A. Safa, A.R. Lau, S., Aten, K. Schilling, K.L. Bales, V. Miller, J. Fitzgerald, M. Chen, K. Hill, K. Dzwigalski, K. Obrietan, M.A. Phelps, W. Sadee, J. Oberdick. Pharmacological prevention of neonatal opioid withdrawal in a pregnant guinea pig model. Front. Pharmacol, DOI: 10.3389/fphar.2020.613328 (2021)

Targeting Ship2-Sam with peptide ligands: Novel insights from a multidisciplinary approach

The lipid phosphatase Ship2 binds the EphA2 receptor through a heterotypic Sam-Sam (Sterile alpha motif) interaction. Inhibitors of the Ship2-Sam/EphA2-Sam complex hold a certain potential as novel anticancer agents. The previously reported “KRI3” peptide binds Ship2-Sam working as a weak antagonist of the EphA2-Sam/Ship2-Sam interaction. Herein, the design and functional evaluation of KRI3 analogues, both linear and cyclic, are described. A multidisciplinary study was conducted through computational docking techniques, and conformational analyses by CD and NMR spectroscopies. The ability of new peptides to bind Ship2-Sam was analysed by NMR, MST and SPR assays. Studies on linear KRI3 analogues pointed out that aromatic interactions through tyrosines are important for the association with Ship2-Sam whereas, an increase of the net positive charge of the sequence or peptide cyclization through a disulfide bridge can favour unspecific interactions without a substantial improvement of the binding affinity to Ship2-Sam. Interestingly, preliminary cell-based assays demonstrated KRI3 cellular uptake even without the conjugation to a cell penetrating sequence with a main cytosolic localization. This work highlights important features of the KRI3 peptide that can be further exploited to design analogues able to hamper Sam-Sam interactions driven by electrostatic contacts.

Identification and quantification of the combined phytotoxicity of one element with various valences: Cr(III) and Cr(VI) for barley root elongation as an example

There is uncertainty in quantifying the toxic effects of total chromium (Cr) in the environment by modeling the toxicity of individual Cr(III) or Cr(VI). In the present study, the effects of Cr(III) and Cr(VI) on barley root elongation were investigated in a hydroponic system where Cr(III) and Cr(VI) combination dose-response experiments under monotoxicity concentration, single-dose addition, and fixed concentration ratios were designed to identify and quantify their combined phytotoxicity of one element with various valences. The results show that the calculated mixed toxicity unit values for 50% inhibition (TUmix50) ranged from 1.06 to 1.45, indicating the weak antagonism effects of Cr(III) and Cr(VI) on barley root toxicity. Also, the single-dose group experiment has proved that the EC50 of Cr(VI) was increased from 71.2 μM to 119.9 μM with Cr(III) addition, which suggested that Cr(III) has antagonism on the toxicity of Cr(VI). While EC50 of Cr(III) was not affected by Cr(VI) addition. After introducing the expansion coefficient of Cr(III) on Cr(VI) toxicity, both the extended concentration addition model (e-CA) based on the log-logistic and Weibull equations and the extended independent action model (e-IA) could more accurately predict the barley root elongation under Cr(III) and Cr(VI) interaction. The e-CA model based on the Weibull equation had almost the best correlation coefficient (R2) and lowest root mean square error (RMSE) between the measured and predicted values. Finally, the combined toxicity and antagonism of the same element with co-existing different valences simultaneously were successfully and firstly identified and quantified in the present study.

Interaction of A3 adenosine receptor ligands with the human multidrug transporter ABCG2

Various adenosine receptor nucleoside-like ligands were found to modulate ATP hydrolysis by the multidrug transporter ABCG2. Both ribose-containing and rigidified (N)-methanocarba nucleosides (C2-, N6- and 5′-modified), as well as adenines (C2-, N6-, and deaza modified), were included. 57 compounds out of 63 tested either stimulated (50) or inhibited (7) basal ATPase activity. Structure-activity analysis showed a separation of adenosine receptor and ABCG2 activities. The 7-deaza modification had favorable effects in both (N)-methanocarba nucleosides and adenines. Adenine 37c (MRS7608) and (N)-methanocarba 7-deaza-5′-ethyl ester 60 (MRS7343) were found to be potent stimulators of ABCG2 ATPase activity with EC50 values of 13.2 ± 1.7 and 13.2 ± 2.2 nM, respectively. Both had affinity in the micromolar range for A3 adenosine receptor and lacked the 5′-amide agonist-enabling group (37c was reported as a weak A3 antagonist, Ki 6.82 μM). Compound 60 significantly inhibited ABCG2 substrate transport (IC50 0.44 μM). Docking simulations predicted the interaction of 60 with 21 residues in the drug-binding pocket of ABCG2.

Relaxin family peptide receptors in GtoPdb v.2021.3

Relaxin family peptide receptors (RXFP, nomenclature as agreed by the NC-IUPHAR Subcommittee on Relaxin family peptide receptors [18, 81]) may be divided into two pairs, RXFP1/2 and RXFP3/4. Endogenous agonists at these receptors are heterodimeric peptide hormones structurally related to insulin: relaxin-1, relaxin, relaxin-3 (also known as INSL7), insulin-like peptide 3 (INSL3) and INSL5. Species homologues of relaxin have distinct pharmacology and relaxin interacts with RXFP1, RXFP2 and RXFP3, whereas mouse and rat relaxin selectively bind to and activate RXFP1 [184]. relaxin-3 is the ligand for RXFP3 but it also binds to RXFP1 and RXFP4 and has differential affinity for RXFP2 between species [183]. INSL5 is the ligand for RXFP4 but is a weak antagonist of RXFP3. relaxin and INSL3 have multiple complex binding interactions with RXFP1 [189] and RXFP2 [91] which direct the N-terminal LDLa modules of the receptors together with a linker domain to act as a tethered ligand to direct receptor signaling [186]. INSL5 and relaxin-3 interact with their receptors using distinct residues in their B-chains for binding, and activation, respectively [225, 104].

Enantiomers of 4-aminopentanoic acid act as false GABAergic neurotransmitters and impact mouse behavior.

Imbalance in the metabolic pathway linking excitatory and inhibitory neurotransmission has been implicated in multiple psychiatric and neurologic disorders. Recently, we described enantiomer-specific effects of 2-methylglutamate, which is not decarboxylated to the corresponding methyl analogue of gamma-aminobutyric acid (GABA): 4-aminopentanoic acid (4APA). Here, we tested the hypothesis that 4APA also has enantiomer-specific actions in brain. Mouse cerebral synaptosome uptake (nmol/mg protein over 30min) of (R)-4APA or (S)-4APA was time and temperature dependent; however, the R enantiomer had greater uptake, reduction of endogenous GABA concentration, and release following membrane depolarization than did the S enantiomer. (S)-4APA exhibited some weak agonist (GABAA α4β3δ, GABAA α5β2γ2, and GABAB B1/B2) and antagonist (GABAA α6β2γ2) activity while (R)-4APA showed weak agonist activity only with GABAA α5β2γ2. Both 4APA enantiomers (100mg/kg IP) were detected in mouse brain 10min after injection, and by 1hr had reached concentrations that were stable over 6hr; both enantiomers were cleared rapidly from mouse serum over 6hr. Two-month-old mice had no mortality following 100-900mg/kg IP of each 4APA enantiomer but did have similar dose-dependent reduction in distance moved in a novel cage. Neither enantiomer at 30 or 100mg/kg impacted outcomes in 23 measures of well-being, activity chamber, or withdrawal from hot plate. Our results suggest that enantiomers of 4APA are active in mouse brain, and that (R)-4APA may act as a novel false neurotransmitter of GABA. Future work will focus on disease models and on possible applications as neuroimaging agents.

Split tibialis anterior tendon transfer to treat ambulatory children with spastic cerebral palsy who experienced dynamic equino varus deformity

Background: Treatment of ambulatory children with spastic cerebral palsy complaining from dynamic equino varus deformity by split tibialis anterior tendon transfer (STATT), because over activity of tibialis anterior muscle and weak antagonist muscles are the main cause of the deformity. Aim: The purpose of this study is to assess the postoperative results of split tibialis anterior tendon transfer, according to Garceau and Palmer criteria. Patients and Methods: 13 feet in 13 ambulatory children with spastic cerebral palsy complaining from dynamic equino varus deformity, preoperatively 7 of the fair,6 of them were poor, while postoperatively 2 of them became excellent,10 of them good and 1 of the fair. Results: The result of this prospective case series study assessed by using Garceau and Palmer criteria. Conclusion: Split tibialis anterior tendon transfer, is a good method for treating ambulatory children with spastic cerebral palsy complaining of dynamic equinovarus deformity of the forefoot and midfoot which is due to overactivity of tibialis anterior muscle and weak antagonists. Keywords: Dynamic equinovarus foot deformity; Split tibialis anterior tendon transfer; Hoffer’s procedure; and Garceau & Palmer criteria.

The action of aripiprazole and brexpiprazole at the receptor level in singultus.

The hiccup (Latin singultus) is an involuntary periodic contraction of the diaphragm followed by glottic closure, which can be a rare side effect of aripiprazole. In contrast to the structurally closely related aripiprazole, brexpiprazole was not associated with this particular adverse drug reaction. Having two very similar drugs that differ in their ability to induce hiccups represents a unique opportunity to gain insight into the receptors involved in the pathophysiology of the symptom and differences in clinical effects between aripiprazole and brexpiprazole. The overlap between maneuvers used to terminate paroxysmal supraventricular tachycardia and those employed to terminate bouts of hiccups suggests that activation of efferent vagal fibers can be therapeutic in both instances. Recent work seems to support a pivotal role for serotonin receptors in such vagal activation. It is unlikely that a unique receptor-drug interaction could explain the different effects of the examined drugs on hiccup. The different effect is most likely the consequence of several smaller effects at more than one receptor. Brexpiprazole is a highly affine (potent) α2C antagonist and, therefore, also an indirect 5-HT1A agonist. In contrast, aripiprazole is a partial 5-HT1A agonist (weak antagonist) and an HT3 antagonist. Activation of 5-HT1A receptors enhances vagal activity while HT3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive.