Selective Antagonist Research Articles

Activation of 5-HT5A receptor in the ventrolateral orbital cortex produces antinociceptive effects in rat models of neuropathic and inflammatory pain

The ventrolateral orbital cortex (VLO) is identified as an integral component of the endogenous analgesic system comprising a spinal cord - thalamic nucleus submedius - VLO - periaqueductal gray (PAG) - spinal cord loop. The present study investigates the effects of 5-HT5A receptor activation in the VLO on allodynia induced by spared nerve injury and formalin-evoked flinching behavior and spinal c-Fos expression in male SD rats, and further examines whether GABAergic modulation is involved in the effects evoked by VLO 5-HT5A receptor activation. We found an upregulation of 5-HT5A receptor expression in the VLO during neuropathic and inflammatory pain states. Microinjection of the non-selective 5-HT5A receptor agonist 5-CT into the VLO dose dependently alleviated allodynia, and flinching behavior and spinal c-Fos expression, which were blocked by the selective 5-HT5A receptor antagonist SB-699551. Moreover, application of the GABAA receptor antagonist bicuculline in the VLO augmented the analgesic effects induced by 5-CT in neuropathic and inflammatory pain states, whereas the GABAA receptor agonist muscimol attenuated these analgesic effects. Additionally, the 5-HT5A receptors were found to be colocalized with GABAergic neurons in the VLO. These results provide new evidence for the involvement of central 5-HT5A receptors in the VLO in modulation of neuropathic and inflammatory pain and support the hypothesis that activation of 5-HT5A receptors may inhibit the inhibitory effect of GABAergic interneurons on output neurons projecting to the PAG (GABAergic disinhibitory mechanisms), consequently activating the brainstem descending inhibitory system that depresses nociceptive transmission at the spinal cord level.

The role of beta-adrenoreceptors in postoperative ileus in rats

The aim of the research was to evaluate the influence of antagonists of specific beta-adrenergic receptor subtypes on bowel motility following abdominal surgery in rat model of postoperative ileus. Bowel motility was measured by the intestinal transit of Evans blue introduced via orogastric tube after surgical procedures of skin incision, laparotomy and laparotomy with gut manipulation. Male rats were given individual adrenergic receptor subtypes antagonists intraperitoneally, and the influence of administered agents on intestinal transit of Evans blue was then evaluated. No statistically significant differences in the length of intestine in tested rats were observed. Propranolol administered prior to surgical procedure has shown protective effect on Evans blue migration in rats undergoing laparotomy and gut manipulation. Intestinal dye transit for propranolol doses of 10, 30 and 45 mg/kg was 18.00 ± 1.88c m, 23.75 ± 1.71 cm and 22.5 ± 2.43 cm, respectively, and for last two doses, statistically significant increase of dye passage was noted, compared to Evans blue transit of 11.00 ± 2.43 cm in the control group. No acceleration of dye migration was seen following administration of beta1-, beta2- and beta3-selective adrenergic receptor antagonist metoprolol, ICI 118.551 and SR58894A, respectively. Our research confirmed that propranolol at high doses, as seen by other researchers, improved bowel motility in early phase of postoperative ileus. That slight acceleration of intestinal dye transit after surgery with gut manipulation is rather connected with membrane-stabilizing action, than the receptor blocking effect, as this effect was not observed after the application of selective antagonists of respective subtypes of beta-adrenergic receptor.

Inhibitory potential of furanocoumarins against cyclin dependent kinase 4 using integrated docking, molecular dynamics and ONIOM methods

Cyclin Dependent Kinase 4 (CDK4) is vital in the process of cell-cycle and serves as a G1 phase checkpoint in cell division. Selective antagonists of CDK4 which are in use as clinical chemotherapeutics cause various side-effects in patients. Furanocoumarins induce anti-cancerous effects in a range of human tumours. Therefore, targeting these compounds against CDK4 is anticipated to enhance therapeutic effectiveness. This work intended to explore the CDK4 inhibitory potential of 50 furanocoumarin molecules, using a comprehensive approach that integrates the processes of docking, drug-likeness, pharmacokinetic analysis, molecular dynamics simulations and ONIOM (Our own N-layered Integrated molecular Orbital and Molecular mechanics) methods. The top five best docked compounds obtained from docking studies were screened for subsequent analysis. The molecules displayed good pharmacokinetic properties and no toxicity. Epoxybergamottin, dihydroxybergamottin and notopterol were found to inhabit the ATP-binding zone of CDK4 with substantial stability and negative binding free energy forming hydrogen bonds with key catalytic residues of the protein. Notopterol exhibiting the highest binding energy was subjected to ONIOM calculations wherein the hydrogen bonding interactions were retained with significant negative interaction energy. Hence, through these series of computerised methods, notopterol was screened as a potent CDK4 inhibitor and can act as a starting point in successive processes of drug design. Communicated by Ramaswamy H. Sarma

Evaluation of aprepitant as an add-on therapy for prevention of chemotherapy induced nausea and vomiting in children

Background: Chemotherapy-induced nausea and vomiting (CINV), represents a common and distressing side effect associated with antineoplastic treatment in pediatric patients. Aprepitant, a selective neurokinin-1 receptor antagonist, is recommended for preventing CINV in combination with a standard antiemetic regimen in children undergoing chemotherapy. This study aimed to evaluate the effectiveness of aprepitant as an add-on therapy to the standard antiemetic regimen for the prevention of CINV in children. Methods: This randomized control study was conducted in the BSMMU, Dhaka, Bangladesh from February 2020 to October 2020. Forty-six children with malignancy undergoing chemotherapy were divided into two arms: the Aprepitant arm (23 patients receiving granisetron, dexamethasone, and aprepitant) and the control arm (23 patients receiving Granisetron and Dexamethasone). Data were analyzed using SPSS version 22.0. Results: The complete response rates for the aprepitant versus control arm during the acute and overall phase were 82% vs. 40% (p=0.003) and 65% vs. 26% (p=0.008), respectively. However, a higher percentage of patients who achieved complete response in the delayed phase was also observed, though statistically not significant (65% vs 40%, p=0.077). In the acute phase, there was a significant reduction in mild to moderate vomiting in the Aprepitant arm as compared to the control arm (p=0.01). In the overall phase, 35% of patients in the Aprepitant arm had mild to moderate vomiting as compared to 74% in the control group (p=0.027). No major adverse effects were reported by patients or caregivers. Conclusions: Adding Aprepitant to the standard antiemetic regimen was effective and safe in preventing CINV, especially in the acute phase, in pediatric patients receiving the moderately and highly emetogenic chemotherapy (HEC).

P2 purinergic receptors regulate the progression of colorectal cancer.

More and more studies have revealed that P2 purinergic receptors play a key role in the progression of colorectal cancer (CRC). P2X and P2Y purinergic receptors can be used as promoters and regulators of CRC and play a dual role in the progression of CRC. CRC microenvironment is rich in ATP and its cleavage products (ADP, AMP, Ado), which act as activators of P2X and P2Y purinergic receptors. The activation of P2X and P2Y purinergic receptors regulates the progression of CRC mainly by regulating the function of immune cells and mediating different signal pathways. In this paper, we focus on the specific mechanisms and functional roles of P2X7, P2Y12, and P2Y2 receptors in the growth and progression of CRC.The antagonistic effects of these selective antagonists of P2X purinergic receptors on the growth, invasion, and metastasis of CRC were further discussed. Moreover, different studies have reported that P2X7 receptor can be used as an effective predictor of patients with CRC.All these indicate that P2 purinergic receptors are a key regulator of CRC.Therefore, antagonizing P2 purinergic receptors may be an innovative treatment for CRC.

Polygenic response of sex chromosomes to sexual antagonism.

Sexual antagonism occurs when males and females differ in their phenotypic fitness optima but are constrained in their evolution to these optima because of their shared genome. The sex chromosomes, which have distinct evolutionary "interests" relative to the autosomes, are theorized to play an important role in sexually antagonistic conflict. However, the evolutionary responses of sex chromosomes and autosomes have usually been considered independently, that is, via contrasting the response of a gene located on either an X chromosome or an autosome. Here, we study the coevolutionary response of the X chromosome and autosomes to sexually antagonistic selection acting on a polygenic phenotype. We model a phenotype initially under stabilizing selection around a single optimum, followed by a sudden divergence of the male and female optima. We find that, in the absence of dosage compensation, the X chromosome promotes evolution toward the female optimum, inducing coevolutionary male-biased responses on the autosomes. Dosage compensation obscures the female-biased interests of the X, causing it to contribute equally to male and female phenotypic change. We further demonstrate that fluctuations in an adaptive landscape can generate prolonged intragenomic conflict and accentuate the differential responses of the X and autosomes to this conflict.

Solubility Enhancement and Formulation Development of an Oral Film of Ondansetron Hydrochloride Monohydrate using Mix-solvency Concept

This research paper presents the formulation and evaluation of ondansetron hydrochloride monohydrate oral film using the mix-solvency concept. Ondansetron hydrochloride monohydrate a selective serotonin receptor antagonist is commonly prescribed to prevent chemotherapy or surgery-induced nausea and vomiting. The aim of the study was to enhance the solubility of ondansetron hydrochloride monohydrate which has been enhanced by the blend of varying aqueous solubilizers poly ethylene glycol, niacinamide, and caffeine. The oral film formulation was prepared using a solvent casting method, incorporating polymers, plasticizers and different solvents. Various formulation variables, including solvent type and concentration, polymer-to-plasticizer ratios, and drug loading, were optimized systematically the resulting oral film was investigated for various parameters such as thickness, drug content, disintegration time, folding endurance and surface pH. The % in-vitro release of drug of the best two formulations F3 and F5 was 99.70 and 96.62%, respectively.

Role of endothelin ETA receptors in the hypertension induced by the VEGFR-2 kinase inhibitors axitinib and lenvatinib in conscious freely-moving rats

Receptor tyrosine kinase inhibitors (RTKIs) suppress tumour growth by targeting vascular endothelial growth factor receptor 2 (VEGFR-2) which is an important mediator of angiogenesis. Here, we demonstrate that two potent RTKIs, axitinib and lenvatinib, are associated with hypertensive side effects. Doppler flowmetry was used to evaluate regional haemodynamic profiles of axitinib and lenvatinib. Male Sprague Dawley rats (350–500 g) were instrumented with Doppler flow probes (renal and mesenteric arteries and descending abdominal aorta) and catheters (jugular vein and distal abdominal aorta, via the caudal artery). Rats were dosed daily with axitinib (3 or 6 mg.kg−1) or lenvatinib (1 or 3 mg.kg−1) and regional haemodynamics were recorded over a maximum of 4 days. Both RTKIs caused significant (p < 0.05) increases in mean arterial pressure (MAP), which was accompanied by significant (p < 0.05) vasoconstriction in both the mesenteric and hindquarters vascular beds. To gain insight into the involvement of endothelin-1 (ET-1) in RTKI-mediated hypertension, we also monitored heart rate (HR) and MAP in response to axitinib or lenvatinib in animals treated with the ETA receptor selective antagonist sitaxentan (5 mg.kg−1) or the mixed ETA/ETB receptor antagonist bosentan (15 mg.kg−1) over two days. Co-treatment with bosentan or sitaxentan markedly reduced the MAP effects mediated by both RTKIs (p < 0.05). Bosentan, but not sitaxentan, also attenuated ET-1 mediated increases in HR. These data suggest that selective antagonists of ETA receptors may be appropriate to alleviate the hypertensive effects of axitinib and lenvatinib.

Copaifera langsdorffii Desf. tree oleoresin-induced antinociception recruits µ1- and κ -opioid receptors in the ventrolateral columns of the periaqueductal gray matter

Popular medicine has been using oleoresin from several species of copaíba tree for the treatment of various diseases and its clinical administration potentially causes antinociception. Electrical stimulation of ventrolateral (vlPAG) and dorsolateral (dlPAG) columns of the periaqueductal gray matter also causes antinociception. The aim this study was to verify the antinociceptive effect of oleoresin extracted from Copaifera langsdorffii tree and to test the hypothesis that oleoresin-induced antinociception is mediated by µ1- and κ-opioid receptors in the vlPAG and dlPAG. Nociceptive thresholds were determined by the tail-flick test in Wistar rats. The copaíba tree oleoresin was administered at different doses (50, 100 and 200 mg/kg) through the gavage technique. After the specification of the most effective dose of copaíba tree oleoresin (200 mg/kg), rats were pretreated with either the µ1-opioid receptor selective antagonist naloxonazine (at 0.05, 0.5 and 5 µg/ 0.2 µl in vlPAG, and 5 µg/ 0.2 µl in dlPAG) or the κ-opioid receptor selective antagonist nor-binaltorphimine (at 1, 3 and 9 nmol/ 0.2 µl in vlPAG, and 9 nmol/ 0.2 µl in dlPAG). The blockade of µ1 and κ opioid receptors of vlPAG decreased the antinociception produced by copaíba tree oleoresin. However, the blockade of these receptors in dlPAG did not alter copaíba tree oleoresin-induced antinociception. These data suggest that vlPAG µ1 and κ opioid receptors are critically recruited in the antinociceptive effect produced by oleoresin extracted from Copaifera langsdorffii.

Real-world evidence on levodopa dose escalation in patients with Parkinson's disease treated with istradefylline.

Istradefylline, a selective adenosine A2A receptor antagonist, is indicated in the US and Japan as adjunctive treatment to levodopa/decarboxylase inhibitors in adults with Parkinson's disease (PD) experiencing OFF time. This study aimed to observe patterns of dose escalation of levodopa over time in patients initiated on istradefylline. Using Japanese electronic health record data, interrupted time series analyses were used to compare levodopa daily dose (LDD, mg/day) gradients in patients before and after initiation of istradefylline. Data were analyzed by period relative to istradefylline initiation (Month 1): pre-istradefylline (Months -72 to 0), early istradefylline (Months 1 to 24), and late istradefylline (Months 25 to 72). Subgroup analyses included LDD before istradefylline initiation (<400, ≥400 to <600, ≥600 mg/day) and treatment with or without monoamine oxidase-B (MAO-B) inhibitors, catechol-O-methyltransferase (COMT) inhibitors, or dopamine agonists before istradefylline initiation. The analysis included 4026 patients; mean (SD) baseline LDD was 419.27 mg (174.19). Patients receiving ≥600 mg/day levodopa or not receiving MAO-B inhibitors or COMT inhibitors demonstrated a significant reduction in LDD increase gradient for pre-istradefylline vs late-phase istradefylline (≥600 mg/day levodopa, -6.259 mg/day each month, p<0.001; no MAO-B inhibitors, -1.819 mg/day each month, p = 0.004; no COMT inhibitors, -1.412 mg/day each month, p = 0.027). This real-world analysis of Japanese prescription data indicated that slowing of LDD escalation was observed in patients initiated on istradefylline, particularly in those receiving ≥600 mg/day levodopa, suggesting istradefylline may slow progressive LDD increases. These findings suggest that initiating istradefylline before other levodopa-adjunctive therapies may mitigate LDD increases, potentially reducing occurrence or severity of levodopa-induced complications in long-term istradefylline treatment.

The P2Y2 receptor mediates terminal adipocyte differentiation and insulin resistance: Evidence for a dual G-protein coupling mode

Several P2Y nucleotide receptors have been shown to be involved in the early stage of adipocyte differentiation in vitro and insulin resistance in obese mice; however, the exact receptor subtype(s) and its underlying molecular mechanism in relevant human cells are unclear. Here, using human primary visceral preadipocytes as a model, we found that during preadipocyte-to-mature adipocyte differentiation, the P2Y2 nucleotide receptor (P2Y2R) was the most upregulated subtype among the eight known P2Y receptors and the only one further dramatically upregulated after inflammatory TNFα treatment. Functional studies indicated that the P2Y2R induced intracellular Ca2+, ERK1/2, and JNK signaling but not the p38 pathway. In addition, stimulation of the P2Y2R suppressed basal and insulin-induced phosphorylation of AKT, accompanied by decreased GLUT4 membrane translocation and glucose uptake in mature adipocytes, suggesting a role of P2Y2R in insulin resistance. Mechanistically, we found that activation of P2Y2R did not increase lipolysis but suppressed PIP3 generation. Interestingly, activation of P2Y2R triggered Gi-protein coupling, and pertussis toxin pretreatment largely inhibited P2Y2R-mediated ERK1/2 signaling and cAMP suppression. Further, treatment of the cells with AR-C 118925XX, a selective P2Y2R antagonist, significantly inhibited adipogenesis, and P2Y2R knockout decreased mouse body weight gain with smaller eWAT mass infiltrated with fewer macrophages as compared to wild-type mice in response to a Western diet. Thus, we revealed that terminal adipocyte differentiation and inflammation selectively upregulate P2Y2R expression and that P2Y2R mediates insulin resistance by suppressing the AKT signaling pathway, highlighting P2Y2R as a potential new drug target to combat obesity and type-2 diabetes.

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.

Machine learning models to predict ligand binding affinity for the orexin 1 receptor

The orexin 1 receptor (OX1R) is a G-protein coupled receptor that regulates a variety of physiological processes through interactions with the neuropeptides orexin A and B. Selective OX1R antagonists exhibit therapeutic effects in preclinical models of several behavioral disorders, including drug seeking and overeating. However, currently there are no selective OX1R antagonists approved for clinical use, fueling demand for novel compounds that act at this target. In this study, we meticulously curated a dataset comprising over 1300 OX1R ligands using a stringent filter and criteria cascade. Subsequently, we developed highly predictive quantitative structure-activity relationship (QSAR) models employing the optimized hyper-parameters for the random forest machine learning algorithm and twelve 2D molecular descriptors selected by recursive feature elimination with a 5-fold cross-validation process. The predictive capacity of the QSAR model was further assessed using an external test set and enrichment study, confirming its high predictivity. The practical applicability of our final QSAR model was demonstrated through virtual screening of the DrugBank database. This revealed two FDA-approved drugs (isavuconazole and cabozantinib) as potential OX1R ligands, confirmed by radiolabeled OX1R binding assays. To our best knowledge, this study represents the first report of highly predictive QSAR models on a large comprehensive dataset of diverse OX1R ligands, which should prove useful for the discovery and design of new compounds targeting this receptor.

Targeting Nociceptin/Orphanin FQ receptor to rescue cognitive symptoms in a mouse neuroendocrine model of chronic stress.

Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.

Combined treatment with naloxone and the alpha2 adrenoceptor antagonist atipamezole reversed brain hypoxia induced by a fentanyl-xylazine mixture in a rat model.

Xylazine, a veterinary tranquillizer known by drug users as "Tranq", is being increasingly detected in people who overdose on opioid drugs, indicating enhanced health risk of fentanyl-xylazine mixtures. We recently found that xylazine potentiates fentanyl- and heroin-induced brain hypoxia and eliminates the rebound-like post-hypoxic oxygen increases. Here, we used oxygen sensors coupled with high-speed amperometry in rats of both sexes to explore the treatment potential of naloxone plus atipamezole, a selective α2-adrenoceptor antagonist, in reversing brain (nucleus accumbens) and periphery (subcutaneous space) hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with naloxone (0.2 mg/kg, IV) fully blocked brain and peripheral hypoxia induced by fentanyl (20 μg/kg, IV), but only partially decreased hypoxia induced by a fentanyl-xylazine mixture. Pretreatment with atipamezole (0.25 mg/kg, IV) fully blocked the hypoxic effects of xylazine (1.0 mg/kg, IV), but not fentanyl. Pretreatment with atipamezole + naloxone was more potent than naloxone alone in blocking the hypoxic effects of the fentanyl-xylazine mixture. Both naloxone and naloxone + atipamezole, delivered at the peak of brain hypoxia (3 min post fentanyl-xylazine exposure), reversed the rapid initial brain hypoxia, but only naloxone + atipamezole decreased the prolonged weaker hypoxia. There were no sex differences in the effects of the different drugs and their combinations on brain and peripheral oxygen responses. Results indicate that combined treatment with naloxone and atipamezole is more effective than naloxone alone in reversing the hypoxic effects of fentanyl-xylazine mixtures. Naloxone + atipamezole treatment should be considered in preventing overdoses induced by fentanyl-xylazine mixtures in humans.

Deciphering the Biophysical Properties of Ion Channel Gating Pores by Coumarin-Benzodiazepine Hybrid Derivatives: Selective AMPA Receptor Antagonists.

In the 1980s, the identification of specific pharmacological antagonists played a crucial role in enhancing our comprehension of the physiological mechanisms associated with α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs). The primary objective of this investigation was to identify specific AMPA receptor antagonists, namely 2,3-benzodiazepines, that function as negative allosteric modulators (NAMs) at distinct locations apart from the glutamate recognition site. These compounds have exhibited a diverse array of anticonvulsant properties. In order to conduct a more comprehensive investigation, the study utilized whole-cell patch-clamp electrophysiology to analyze the inhibitory effect and selectivity of benzodiazepine derivatives that incorporate coumarin rings in relation to AMPA receptors. The study's main objective was to acquire knowledge about the relationship between the structure and activity of the compound and comprehend the potential effects of altering the side chains on negative allosteric modulation. The investigation provided crucial insights into the interaction between eight CD compounds and AMPA receptor subunits. Although all compounds demonstrated effective blockade, CD8 demonstrated the greatest potency and selectivity towards AMPA receptor subunits. The deactivation and desensitization rates were significantly influenced by CD8, CD6, and CD5, distinguishing them from the remaining five chemicals. The differences in binding and inhibition of AMPA receptor subunits can be attributed to structural discrepancies among the compounds. The carboxyl group of CD8, situated at the para position of the phenyl ring, substantially influenced the augmentation of AMPA receptor affinity. The findings of this study highlight the potential of pharmaceutical compounds that specifically target AMPA receptors to facilitate negative allosteric modulation.

Solifenacin promotes remyelination in cuprizone mouse model by inhibiting the Wnt/β-catenin signaling pathway

Demyelinating diseases are a type of neurological disorder characterized by the damage to the myelin sheath in the central nervous system. Promoting the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) is crucial for treatment. Non-selective muscarinic receptor (MR) antagonists have been shown to improve remyelination in rodent models, although the mechanisms are still unclear. In this study, we treated cuprizone (CPZ)-induced demyelination mouse model with different concentrations of Solifenacin (Sol), a selective M3 receptor antagonist, to determine the optimal concentration for promoting remyelination. Behavioral tests and Luxol fast blue (LFB) staining were used to observe the extent of remyelination, while immunofluorescence was used to measure the expression levels of myelin-related proteins, including myelin basic protein (MBP) and platelet-derived growth factor receptor alpha (PDGFR-α). Western blot analysis was employed to analyze the expression levels of molecules associated with the Wnt/β-catenin signaling pathway. The results showed that Sol treatment significantly promoted myelin regeneration and OPCs differentiation in CPZ-induced demyelination mouse model. Additionally, Sol treatment inhibited the Wnt/β-catenin signaling pathway and reversed the effects of CPZ on OPCs differentiation. In conclusion, Sol may promote the differentiation of OPCs by inhibiting the Wnt/β-catenin signaling pathway, making it a potential therapeutic option for central nervous system demyelinating diseases.

Deep learning-based design and screening of benzimidazole-pyrazine derivatives as adenosine A2B receptor antagonists

The Adenosine A2B receptor (A2BAR) is considered a novel potential target for the immunotherapy of cancer, and A2BAR antagonists have an inhibitory effect on tumor growth, proliferation, and metastasis. In our previous studies, we identified a class of benzimidazole-pyrazine scaffolds whose derivatives exhibited the antagonistic effect but lacked subtype selectivity towards A2BAR. In this work, we developed a scaffold-based protocol that incorporates a deep generative model and multilayer virtual screening to design benzimidazole-pyrazine derivatives as potential selective A2BAR antagonists. By utilizing a generative model with reported A2BAR antagonists as the training set, we built up a scaffold-focused library of benzimidazole-pyrazine derivatives and processed a virtual screening protocol to discover potential A2BAR antagonists. Finally, five molecules with different Bemis–Murcko scaffolds were identified and exhibited higher binding free energies than the reference molecule 12o. Further computational analysis revealed that the 3-benzyl derivative ABA-1266 presented high selectivity toward A2BAR and showed preferred draggability, providing future potent development of selective A2BAR antagonists. Communicated by Ramaswamy H. Sarma

Cannabidiol at Nanomolar Concentrations Negatively Affects Signaling through the Adenosine A2A Receptor.

Cannabidiol (CBD) is a phytocannabinoid with potential as a therapy for a variety of diseases. CBD may act via cannabinoid receptors but also via other G-protein-coupled receptors (GPCRs), including the adenosine A2A receptor. Homogenous binding and signaling assays in Chinese hamster ovary (CHO) cells expressing the human version of the A2A receptor were performed to address the effect of CBD on receptor functionality. CBD was not able to compete for the binding of a SCH 442416 derivative labeled with a red emitting fluorescent probe that is a selective antagonist that binds to the orthosteric site of the receptor. However, CBD reduced the effect of the selective A2A receptor agonist, CGS 21680, on Gs-coupling and on the activation of the mitogen activated kinase signaling pathway. It is suggested that CBD is a negative allosteric modulator of the A2A receptor.

Esaxerenone Protects against Diabetic Cardiomyopathy via Inhibition of the Chemokine and PI3K-Akt Signaling Pathway.

(1) Background: Diabetic cardiomyopathy (DCM) is a unique form of cardiomyopathy that develops as a consequence of diabetes and significantly contributes to heart failure in patients. Esaxerenone, a selective non-steroidal mineralocorticoid receptor antagonist, has demonstrated potential in reducing the incidence of cardiovascular and renal events in individuals with chronic kidney and diabetes disease. However, the exact protective effects of esaxerenone in the context of DCM are still unclear. (2) Methods: The DCM model was successfully induced in mice by administering streptozotocin (55 mg/kg per day) for five consecutive days. After being fed a normal diet for 16 weeks, echocardiography was performed to confirm the successful establishment of the DCM model. Subsequent sequencing and gene expression analysis revealed significant differences in gene expression in the DCM group. These differentially expressed genes were identified as potential targets for DCM. By utilizing the Swiss Target Prediction platform, we employed predictive analysis to identify the potential targets of esaxerenone. A protein-protein-interaction (PPI) network was constructed using the common targets of esaxerenone and DCM. Enrichment analysis was conducted using Metascape. (3) Results: Compared to the control, the diabetic group exhibited impaired cardiac function and myocardial fibrosis. There was a total of 36 common targets, with 5 key targets. Enrichment analysis revealed that the chemokine and PI3K-Akt signaling pathway was considered a crucial pathway. A target-pathway network was established, from which seven key targets were identified. All key targets exhibited good binding characteristics when interacting with esaxerenone. (4) Conclusion: The findings of this study suggest that esaxerenone exhibits a favorable therapeutic effect on DCM, primarily by modulating the chemokine and PI3K-Akt signaling pathway.