Selective Receptor Antagonist Research Articles

Combined Endocannabinoid and Cyclooxygenase Inhibition Additively Attenuates Post-Surgical Pain.

Introduction: Post-surgical pain arises following a clinical operation, often persisting throughout recovery. While current treatments reduce pain, repeated use increases the probability of adverse events. monoacylglycerol lipase (MAGL) inhibition has previously been shown to produce analgesia, either through CB1 or CB2 mechanisms, dependent on the underlying pain phenotype. Thus, this study investigated the analgesic potential of inhibiting MAGL, alone and in combination with the analgesic non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium in a model of post-surgical pain. Methods: Male and female C57BL/6J mice were subjected to hindpaw incision (HPI) surgery. Mechanical allodynia, climbing, grip strength, and thermal preference were measured 24 h following HPI. The dose-dependent anti-allodynic effects of the MAGL inhibitors (irreversible MAGL inhibitor [JZL184] and selective MAGL inhibitor [MJN110]) and the NSAID diclofenac, as well as the additive potential of combined MAGL and cyclooxygenase (COX) inhibition, were assessed. Selective antagonists of CB1 and CB2 receptors were used to challenge the cannabinoid-receptor mechanism of JZL184. Similarly, the anti-allodynic effects of the CB2-selective agonist (LY2828360) were tested. JZL184 was administered repeatedly to determine tolerance. Finally, hindpaw cytokines were quantified via multiplex ELISA 24 h after HPI surgery. Results: Approximately 24 h post-surgery, the MAGL inhibitors JZL184 (≥4 mg/kg) or MJN110 (≥5 mg/kg), as well as the NSAID diclofenac sodium (≥16.67 mg/kg), attenuated HPI-induced mechanical allodynia, as assessed with von Frey filaments. The anti-allodynic effects of JZL184 (40 mg/kg) were blocked by pre-treatment of the CB2 antagonist SR144528 (3 mg/kg) but not the CB1-selective antagonist rimonabant (SR141716A; 3 mg/kg), suggesting a CB2-mediated mechanism of anti-allodynia via MAGL inhibition. Similarly, LY2828360 (3 mg/kg) reduced HPI-induced allodynia. Moreover, when administered repeatedly, the anti-allodynic effects of JZL184 (8 mg/kg) persisted and did not undergo tolerance. A separate cohort was administered a sub-analgesic dose of JZL184 (1 mg/kg), diclofenac sodium (1.85 mg/kg), or both compounds concurrently. This subthreshold JZL184 and diclofenac sodium combination attenuated HPI-induced allodynia, suggesting an additive drug interaction. Finally, HPI per se increased pro-inflammatory cytokine levels, which were unaltered by MAGL inhibition despite the anti-allodynia assessed behaviorally. Conclusion: These data support simultaneously targeting endocannabinoids and COX enzymes as a potential post-operative pain management approach.

A systematic review and meta-analysis on evaluating the efficacy and safety of netupitant/palonosetron compared to aprepitant for the prevention of chemotherapy-induced nausea and vomiting in patients undergoing emetogenic chemotherapy.

823 Background: NEPA stands as the exclusive oral fixed combination antiemetic agent, comprising the highly selective NK1 receptor antagonist (RA) netupitant (300 mg) and the clinically distinct 5-HT3 RA, palonosetron (0.5 mg). Administered in a single dose, NEPA concurrently modulates two critical antiemetic pathways, offering a more convenient and straightforward alternative for sustained protection against chemotherapy-induced nausea andvomiting (CINV). Numerous studies have assessed NEPA's efficacy relative to other Neurokinin (NK) 1 receptor antagonists (RAs), notably aprepitant (APR), widely utilized for CINV. Our study critically examines the efficacy and safety of NEPA versus APR for preventing CINV in patients receiving emetogenic chemotherapy, drawing insights from recent studies. Methods: Studies comparing NEPA versus APR for the prevention of CINV in patients receiving emetogenic chemotherapy until August 2024 were systematically searched on Medline, Embase, and Cochrane Library. Notably, no systematic review or meta-analysis of pooled data from existing studies is currently present in the literature. Results: Following screening, four studies were deemed eligible for inclusion in the meta-analysis, encompassing a total of 2079 patients. The NEPA group comprised 1047 individuals, while the APR group comprised 1032 subjects. The primary outcome included the comparison of subjects experiencing no nausea in overall phases. Secondary outcomes involved subjects with no emesis and no nausea in the acute and delayed phases. A significant reduction in the risk of overall nausea in the NEPA group was observed compared to the APR group after Moderately Emetogenic Therapy (MEC) or Highly Emetogenic Therapy (HEC) [Risk Ratio (RR) of 1.07, 95% Confidence Interval (CI) = 1.01-1.13, P = 0.01). A trend of reduced emesis during both acute [RR = 1.08, 95% CI = 0.95-1.22, P = 0.24] and delayed periods [RR = 1.03, 95% CI = 0.99-1.07, P = 0.15] was observed in the NEPA group, but the results were not statistically significant. Significant nausea in the acute and delayed post-chemotherapy periods exhibited a similar trend (RR = 1.02, 95% CI = 0.98-1.06, P = 0.43) and (RR = 1.04, 95% CI = 0.98-1.10, P = 0.23) respectively, with non-significant statistical outcomes. Conclusions: Our analysis suggests that the use of NEPA results in better control of nausea in overall phases compared to Aprepitant for the prevention of CINV in patients receiving emetogenic chemotherapy. However, NEPA demonstrates comparable efficacy to aprepitant in achieving control of nausea and emesis when the symptoms are stratified in acute and delayed phases. Nevertheless, further studies are warranted for a comprehensive comparison between NEPA and Aprepitant for the prevention of CINV.

Pharmacodynamic, Safety and Pharmacokinetic Effects of Co-Administration of the Selective Orexin-1 Receptor Antagonist INDV-2000 and Buprenorphine in Treatment Seeking Individuals With Opioid Use Disorder

Pharmacodynamic, Safety and Pharmacokinetic Effects of Co-Administration of the Selective Orexin-1 Receptor Antagonist INDV-2000 and Buprenorphine in Treatment Seeking Individuals With Opioid Use Disorder

Discovery of Brain-Penetrative Negative Allosteric Modulators of NMDA Receptors Using FEP-Guided Structure Optimization and Membrane Permeability Prediction.

N-Methyl-d-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors in the central nervous system (CNS), have garnered attention for their role in brain disorders. Specifically, GluN2A-containing NMDA receptors have emerged as a potential therapeutic target for the treatment of depressive disorders and epilepsy. However, the development of GluN2A-containing NMDA receptor-selective antagonists, represented by N-(4-(2-benzoylhydrazine-1-carbonyl)benzyl)-3-chloro-4-fluorobenzenesulfonamide (TCN-201) and its derivatives, faces a significant challenge due to their limited ability to penetrate the blood-brain barrier (BBB), hampering their in vivo characterization and further advancement. In this study, we reported a series of 2-((5-(phemylamino)-1,3,4-thiadiazol-2-yl)thio)-N-(cyclohexylmethyl)acetamide derivatives, achieved through a structure-guided optimization strategy using free energy perturbation (FEP) and BBB permeability estimation. Through systematic exploration of various phenyl substitutions, compound 1f emerged as a standout compound, demonstrating substantially enhanced inhibitory activity compared with the lead compound TCN-213. Compound 1f not only displayed satisfactory BBB permeability but also showed antidepressant-like potency in the hydrocortisone-induced zebrafish depression-like model. All results position it as a promising candidate for developing innovative therapeutics for NMDA receptor-related disorders.

Transformer-based modeling of Clonal Selection and Expression Dynamics reveals resistance mechanisms in breast cancer

Understanding transcriptional heterogeneity in cancer cells and its implication for treatment response is critical to identify how resistance occurs and may be targeted. Such heterogeneity can be captured by in vitro studies through clonal barcoding methods. We present TraCSED (Transformer-based modeling of Clonal Selection and Expression Dynamics), a dynamic deep learning approach for modeling clonal selection. Using single-cell gene expression and the fitness of barcoded clones, TraCSED identifies interpretable gene programs and the time points at which they are associated with clonal selection. When applied to cells treated with either giredestrant, a selective estrogen receptor (ER) antagonist and degrader, or palbociclib, a CDK4/6 inhibitor, pathways dynamically associated with resistance are revealed. For example, ER activity is associated with positive selection around day four under palbociclib treatment and this adaptive response can be suppressed by combining the drugs. Yet, in the combination treatment, one clone still emerged. Clustering based on partial least squares regression found that high baseline expression of both SNHG25 and SNCG genes was the primary marker of positive selection to co-treatment and thus potentially associated with innate resistance — an aspect that traditional differential analysis methods missed. In conclusion, TraCSED enables associating features with phenotypes in a time-dependent manner from scRNA-seq data.

Compound 38, a novel potent and selective antagonist of adenosine A2A receptor, enhances arousal in mice.

Adenosine A2A receptor (A2AR) plays a pivotal role in the regulation of sleep-wake behaviors. We previously reported an A2AR selective antagonist compound 38 with an IC50 value of 29.0 nM. In this study, we investigated its effect on sleep-wake regulation in mice. Wild-type (WT) mice were administered compound 38 (3.3, 5.0, 7.5, 15, 30 mg/kg, i.p.) at 9:00, and electroencephalography and electromyography were simultaneously recorded. We showed that administration of compound 38 exhibited a dose-dependent effect on wakefulness promotion. To investigate the impact of compound 38 on sleeprebound, we conducted a 6 h (13:00-19:00) sleep deprivation experiment. We found that administration of compound 38 (30 mg/kg) produced a wakefulness-promoting effect lasting for 1 h. Subsequently, we explored the critical role of A2AR in the wakefulness-promoting effect of compound 38 using A2AR knockout (KO) mice and their WT littermates. We found that compound 38 enhanced wakefulness in WT mice, but did not have an arousal-promoting effect in A2AR KO mice, suggesting that the arousal-promoting effect of compound 38 was mediated by A2AR. We conducted immunohistochemistry and selectively ablated A2AR-positive neurons using cell type-specific caspase-3 expression, which revealed an essential role of A2AR-positive neurons in the nucleus accumbens shell for the arousal-promoting effect of compound 38. In conclusion, as a novel A2AR antagonist, compound 38 promotes wakefulness in mice via the A2AR and exhibits promising applications for further advancements in the field of sleep-wake disorders.

Safety and Efficacy of Ecopipam in Patients with Tourette Syndrome: A Systematic Review and Meta-analysis.

Ecopipam is a selective antagonist of the dopamine D1 receptor, and its efficacy and safety have recently been explored in several clinical trials involving patients with Tourette syndrome (TS). The objectives of this systematic review were to determine the pooled estimate for efficacy [in terms of reduction in tic Yale Global Tic Severity Scale (YGTSS) scores] and safety of oral ecopipam in subjects with TS. All clinical trials that explored the efficacy and/or safety of ecopipam in patients with TS were included to determine the pooled estimate for change in YGTSS, Clinical Global Impression (CGI)-TS, and the severity of comorbid attention-deficit hyperactive disorder (ADHD), obsessive compulsion disorder (OCD), and depressive symptoms, as well as the nature and frequency of adverse effects. Case-series, retrospective studies, and case reports were excluded. Databases, such as PUBMED, EMBASE, Cochrane Central Register of Controlled Trials, and SCOPUS were searched to identify these trials using suitable combination of MESH terms/keywords on 15 June 2024. ROB 2.0 and ROBINS-I tool were used to assess the risk of bias in included randomized-controlled trials (RCTs) and non-randomized intervention studies, respectively, and the GRADE system to determine the certainty of the collated evidence. A total of 96 records were identified in the database search and 31 records were screened after removing duplicates. After excluding 23 irrelevant records, the full-text review included 8 records. Finally, six publications from three completed clinical trials (two RCTs, with one having an open-label extension) and one ongoing clinical trial were included. A total of 251 participants were included. The pooled estimate for mean change in YGTSS-TTS from baseline to the completion of the randomization period was statistically better in the ecopipam group compared with the placebo group [mean difference: - 3.0, 95% (confidence interval (CI) - 4.2 to - 1.9, I2 = 55%, p < 0.0001]. The ecopipam group also fared statistically better in terms of YGTSS-motor tic score, phonic tic score, as well as CGI-TS-S (p < 0.0001). Changes in depressive and obsessive-compulsive symptoms were comparable in both groups, as well as the incidence of adverse effects. Ecopipam is effective in reducing theseverity of tics in subjects with TS and has agood safety profile. However, only alimited number of studies were included in thereview, with some having small sample sizes and short duration of follow-up.

Pharmacological modulation of dopamine receptors reveals distinct brain-wide networks associated with learning and motivation in non-human primates.

The neurotransmitter dopamine (DA) has a multifaceted role in healthy and disordered brains through its action on multiple subtypes of dopaminergic receptors. How modulation of these receptors influences learning and motivation by altering intrinsic brain-wide networks remains unclear. Here we performed parallel behavioral and resting-state functional MRI experiments after administration of two different DA receptor antagonists in male and female macaque monkeys. Systemic administration of SCH-23390 (D1 antagonist) slowed probabilistic learning when subjects had to learn new stimulus-reward associations and diminished functional connectivity (FC) in cortico-cortical and fronto-striatal connections. By contrast, haloperidol (D2 antagonist) improved learning and broadly enhanced FC in cortical connections. Further comparisons between the effect of SCH-23390/haloperidol on behavioral and resting-state FC revealed specific cortical and subcortical networks associated with the cognitive and motivational effects of DA manipulation, respectively. Thus, we reveal distinct brain-wide networks that are associated with the dopaminergic control of learning and motivation via DA receptors.Significance Statement D1 and D2 receptors are heavily implicated in cognitive and motivational processes, as well as in a number of psychiatric disorders. Despite this, little is known about how selective manipulation of these different receptors impacts cognition through changing activity across brain-wide intrinsic networks. Here, we examined the acute behavioral and brain-wide effects of D1 and D2 receptor-selective antagonists, SCH-23390 and haloperidol, in macaques performing a probabilistic learning task. SCH administration diminished, and haloperidol improved, animals' task performance. Mirroring these effects on behavior, SCH reduced, and haloperidol increased, the resting-state functional connectivity across brain-wide networks, most notably in the cortico-striatal areas. Thus, our results highlight the opposing effects of D1 and D2 receptor modulation on the brain and behavior.

Inhibition of Glucocorticoid Synthesis by Metyrapone as an Approach to Study Their Contribution to Gastroprotection in Rats

According to the results of our research glucocorticoids produced in response to stress ulcerogenic stimuli are gastroprotective factors. The aim of this review article is to demonstrate, through the analysis of data obtained in our studies, that the inhibition of glucocorticoid synthesis by metyrapone can be an adequate and valuable approach for studying the contribution of glucocorticoids, produced during acute activation of the hypothalamic-pituitary-adrenocortical (HPA) axis, to gastroprotection in rats. When studying the contribution of glucocorticoids produced in response to moderate, normally non-ulcerogenic stressors or to the administration of the corticotropin-releasing factor (CRF) to gastroprotection, it was shown that the suppression of these hormones by metyrapone leads to: 1) the transformation of normally non-ulcerogenic stimuli into ulcerogenic ones; 2) the elimination of the gastroprotective effect of stress preconditioning; 3) the elimination of the gastroprotective effect of CRF. The effects of metyrapone were reproduced under conditions of suppressed glucocorticoid production using the selective CRF-1 receptor antagonist NBI 27914 and the blockade of glucocorticoid receptors with their antagonist RU38486. The data presented suggest that: a) glucocorticoids produced in response to moderate stress stimuli contribute to the protection of the gastric mucosa under these conditions and increase its resistance to subsequent ulcerogenic stimuli (i.e., they contribute to the gastroprotective effect of stress preconditioning); b) glucocorticoids produced in response to CRF administration participate in the realization of its gastroprotective action. The data obtained confirm that the activation of the HPA axis is a gastroprotective component of stress response, and stress-produced glucocorticoids are important gastroprotective factors.

Cannabidiol induces autophagy via CB1 receptor and reduces α-synuclein cytosolic levels.

Numerous studies have explored the role of cannabinoids in neurological conditions, chronic pain and neurodegenerative diseases. Restoring autophagy has been proposed as a potential target for the treatment of neurodegenerative diseases. In our study, we used a neuroblastoma cell line that overexpresses wild-type α-synuclein to investigate the effects of cannabidiol on autophagy modulation and reduction in the level of cytosolic α-synuclein. Our results demonstrated that cannabidiol enhances the accumulation of LC3-II- and GFP-LC3-positive vesicles, which indicates an increase in autophagic flux. In addition, cannabidiol-treated cells showed a reduction in cytosolic α-synuclein levels. These effects were inhibited when the cells were treated with a CB1 receptor-selective antagonist, which indicates that the biological effects of cannabidiol are mediated via its interaction with CB1 receptor. Additionally, we also observed that cannabinoid compounds induce autophagy and α-synuclein degradation after they interact with the CB1 receptor. In summary, our data suggest that cannabidiol induces autophagy and reduces cytosolic α-synuclein levels. These biological effects are mediated preferentially through the interaction of cannabidiol with CB1 receptors, and therefore, cannabinoid compounds that act selectively on this receptor could represent a new approach for autophagy modulation and degradation of protein aggregates.

Formulation, Development and Evaluation of Famotidine Orodispersible Tablets

Aim of the study: The main objective of present research work is to formulate the famotidine orodispersible tablets. Famotidine is a selective H2 receptor antagonist or H2 blocker belongs to BCS Class-II and is used to treat heartburn and duodenal ulcers. Materials and methods: The Orodispersible tablets of famotidine were prepared employing different concentrations of sodium starch glycolate, Crospovidone and Croscarmellose sodium in different combinations as superdisintegrants by direct compression. Mannitol and sodium saccharine were added to microcrystalline cellulose Magnesium stearate as a diluent to improve the organoleptic qualities of the tablets. using 23 factorial design mothod was used to formulate orodispersible tablet. Prepared tablets were then subjected to different tests for tablets like Wetting time, Water absorption ratio in-vitro disintegration time, thickness, diameter, hardness, friability, weight variation, drug content, and in-vitro dissolution study were all assessed for the tablets. Design expert study was conducted to know the interaction between different superdisintegrants and to select best optimized formulation in among all formulations. Results: The tablets' good mechanical strength was indicated by the hardness and friability data. The tablets quickly dispersed in the mouth in less than 12 seconds, according to the F5 in vitro disintegration time results respectively, and 99.24% of the drug release in 15 minutes. The optimal formulations of Famotidine Orodispersible tablets for enhancing the drug's bioavailability and onset of action were determined to be F5. Conclusion: The optimized formulation showed increased drug release compared to commercially available orodispersible tablets. No changes in disintegration time, drug content and in in vitro drug release from optimized formulation on storage for 1months at 40°C ± 2°C /75% RH ± 5% RH were observed during stability studies which confirmed the stability of the optimized formulation.

TRAP-Induced Platelet Reactivity Is Inhibited by Omega-3 Fatty Acid-Derived Prostaglandin E3 (PGE3).

Background: Prostaglandins are naturally occurring local mediators that can participate in the modulation of the cardiovascular system through their interaction with Gs/Gi-coupled receptors in different tissues and cells, including platelets. Thrombin is one of the most important factors that regulates platelet reactivity and coagulation. Clinical trials have consistently shown that omega-3 fatty acid supplementation lowers the risk for cardiovascular mortality and morbidity. Since omega-3 fatty acids are the main precursors of PGE3 in vivo, it would be relevant to investigate the effects of PGE3 on Thrombin Receptor Activating Peptide (TRAP-6)-induced platelet reactivity to determine the receptors and possible mechanisms of action of these compounds. Methods: We have measured platelet aggregation, P-selectin expression, and vasodilator-stimulated phosphoprotein (VASP) phosphorylation to evaluate platelet reactivity induced by TRAP-6 to determine the effects of PGE3 on platelet function. Results: We assessed the ability of DG-041, a selective prostanoid EP3 receptor antagonist, and of ONO-AE3-208, a selective prostanoid EP4 receptor antagonist, to modify the effects of PGE3. PGE3 inhibited TRAP-6-induced platelet aggregation and activation. This inhibition was enhanced in the presence of a Gi-coupled EP3 receptor antagonist and abolished in the presence of a Gs-coupled EP4 receptor antagonist. The effects of PGE3 were directly related to changes in cAMP, assessed by VASP phosphorylation. Conclusions: The general effects of PGE3 on human platelet reactivity are the consequence of a balance between activatory and inhibitory effects at receptors that have contrary effects on adenylate cyclase. These results indicate a potential mechanism by which omega-3 fatty acids underlie cardioprotective effects.

The study of TRPV1 channelsof the central nervous systemand their effect on anxiety in ICR mice

The TRPV1 channel is actively involved in various neuronal processes and is found in various structures of the nervous system, including peripheral and central neurons, sensory ganglia, spinal cord and various parts of the brain. Due to its ability to respond to various stimuli, TRPV1 can have a significant impact on the body’s responses to stress. Studies indicate the involvement of TRPV1 in the regulation of anxiety behavior. Suppression of TRPV1 activity leads to a decrease in the level of anxiety in animals, which indicates the importance of this channel in psychoemotional regulation. A promising compound for inhibiting this channel is the APHC3 peptide, which is a selective receptor antagonist. The results obtained in the course of our study show that this peptide has a pronounced anxiolytic effect, reducing the level of anxiety in the studied animals.

Hederagenin is a Highly Selective Antagonist of the Neuropeptide FF Receptor 1 that Reveals Mechanisms for Subtype Selectivity

AbstractRF‐amide peptide receptors including the neuropeptide FF receptor 1 (NPFFR1) are G protein‐coupled receptors (GPCRs) that modulate diverse physiological functions. High conservation of endogenous ligands and receptors makes the identification of selective ligands challenging. Previously identified antagonists mimic the C‐terminus of peptide ligands and lack selectivity towards the closely related neuropeptide FF receptor 2 (NPFFR2) or the neuropeptide Y1 receptor (Y1R). In a high‐throughput screening, we identified the pentacyclic triterpenoid hederagenin (1) as a novel selective antagonist for the NPFFR1. Hederagenin (1) is a natural product isolated from Hedera helix (ivy). We characterized its mode of activity using in vitro and in silico methods, revealing an overlapping binding site of the small molecule with the orthosteric peptide agonists. Despite the high similarity of the orthosteric binding pockets of NPFFR1 and NPFFR2, hederagenin (1) shows strong subtype selectivity, particularly caused by slight differences in the shape of the binding pockets and the rigidity of the small molecule. Several residues inhibiting the activity of hederagenin (1) at the NPFFR2 were identified. As NPFFR1 antagonists are discussed as potential candidates for the treatment of chronic pain, these insights into the structural determinants governing subtype specificity will facilitate the development of next‐generation analgesics with improved safety and efficacy.

Hederagenin is a Highly Selective Antagonist of the Neuropeptide FF Receptor 1 that Reveals Mechanisms for Subtype Selectivity.

RF-amide peptide receptors including the neuropeptide FF receptor 1 (NPFFR1) are G protein-coupled receptors (GPCRs) that modulate diverse physiological functions. High conservation of endogenous ligands and receptors makes the identification of selective ligands challenging. Previously identified antagonists mimic the C-terminus of peptide ligands and lack selectivity towards the closely related neuropeptide FF receptor 2 (NPFFR2) or the neuropeptide Y1 receptor (Y1R). In a high-throughput screening, we identified the pentacyclic triterpenoid hederagenin (1) as a novel selective antagonist for the NPFFR1. Hederagenin (1) is a natural product isolated from Hedera helix (ivy). We characterized its mode of activity using in vitro and in silico methods, revealing an overlapping binding site of the small molecule with the orthosteric peptide agonists. Despite the high similarity of the orthosteric binding pockets of NPFFR1 and NPFFR2, hederagenin (1) shows strong subtype selectivity, particularly caused by slight differences in the shape of the binding pockets and the rigidity of the small molecule. Several residues inhibiting the activity of hederagenin (1) at the NPFFR2 were identified. As NPFFR1 antagonists are discussed as potential candidates for the treatment of chronic pain, these insights into the structural determinants governing subtype specificity will facilitate the development of next-generation analgesics with improved safety and efficacy.

Stress and obesity signaling converge on CREB phosphorylation to promote pancreatic cancer.

One of the deadliest types of cancer is pancreatic ductal adenocarcinoma (PDAC). Chronic stress and obesity are recognized as risk factors for PDAC. We hypothesized that the combination of stress and obesity strongly promotes pancreatic cancer development and growth. Here, we show that the stress mediator norepinephrine and the beta adrenergic receptor agonist isoproterenol rapidly stimulate CREB phosphorylation at Ser133 in human PDAC cells. Exposure to the non-selective beta adrenergic receptor antagonist propranolol or selective antagonists, including nebivolol, atenolol, or ICI118551 blocked CREB phosphorylation elicited by norepinephrine or isoproterenol in PDAC cells. Stimulation of PDAC cells with neurotensin, a neuropeptide implicated in obesity and PDAC, also stimulated CREB phosphorylation at Ser133. Mechanistically, norepinephrine induced CREB phosphorylation at Ser133 via PKA whereas neurotensin promoted CREB phosphorylation predominantly through protein kinase D (PKD). Our results indicate that CREB is a point of signal convergence that mediates proliferation in PDAC cells and raised the possibility that stress and diet cooperate in promoting PDAC in vivo. To test this notion, mice expressing KrasG12D in all pancreatic lineages (KC mice) and fed an obesogenic high fat, calorie diet (HFCD) that promotes early PDAC development were subjected to social isolation stress (SIS). We show that SIS induced a significant increase in the proportion of advanced PDAC precursor lesions (pancreatic intraepithelial neoplasia [PanIN]-3) in KC mice subjected to an obesogenic HFCD. Implications: Our data imply that chronic (social isolation) stress cooperates with diet-induced obesity in accelerating the development of pancreatic cancer.

Endothelin receptor antagonists in chronic kidney disease.

Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ETA) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ETA ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ETAreceptor andangiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ETA-selective ERA, zibotentan, with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice.

E-52862-A selective sigma-1 receptor antagonist, in peripheral neuropathic pain: Two randomized, double-blind, phase 2 studies in patients with chronic postsurgical pain and painful diabetic neuropathy.

We report the efficacy and safety of E-52862-a selective, sigma-1 receptor antagonist-from phase 2, randomized, proof-of-concept studies in patients with moderate-to-severe, neuropathic, chronic postsurgical pain (CPSP) and painful diabetic neuropathy (PDN). Adult patients (CPSP [N = 116]; PDN [N = 163]) were randomized at a 1:1 ratio to 4 weeks of treatment with E-52862 (CPSP [n = 55]; PDN [n = 85]) or placebo (CPSP [n = 61]; PDN [n = 78]) orally once daily. Pain intensity scores were measured using a numerical pain rating scale from 0 (no pain) to 10 (worst pain imaginable). The primary analysis population comprised patients who received study drug with ≥1 baseline and on-treatment observation (full analysis set). In CPSP, mean baseline average pain was 6.2 for E-52862 vs. 6.5 for placebo. Week 4 mean change from baseline (CFB) for average pain was -1.6 for E-52862 vs. -0.9 for placebo (least squares mean difference [LSMD]: -0.9; p = 0.029). In PDN, mean baseline average pain was 5.3 for E-52862 vs. 5.4 for placebo. Week 4 mean CFB for average pain was -2.2 for E-52862 vs. -2.1 for placebo (LSMD: -0.1; p = 0.766). Treatment-emergent adverse events (TEAEs) were reported in 90.9% of E-52862-treated patients vs. 76.7% of placebo-treated patients in CPSP and 34.1% vs. 26.9% in PDN. Serious TEAEs occurred in CPSP only: E-52862: 5.5%; placebo: 6.7%. E-52862 demonstrated superior relief of CPSP vs. placebo after 4 weeks. Reductions in pain intensity were seen in PDN with E-52862; high placebo response rates may have prevented differentiation between treatments. E-52862 had acceptable tolerability in both populations. These proof-of-concept studies validate the mode of action of E-52862, a selective sigma-1 receptor antagonist. In CPSP, E-52862 resulted in clinically meaningful pain relief. In PDN, reductions in pain intensity were seen with E-52862; high placebo response rates may have prevented differentiation between E-52862 and placebo. These findings are clinically relevant given that neuropathic pain is highly incapacitating, lacking effective treatments and representing a significant unmet medical need, and support further development of sigma-1 receptor antagonists for peripheral neuropathic pain.

Orexants, Orexin Receptor Antagonists: Novel Therapeutic Agents for Insomnia Disorder

Insomnia is when a person feels difficulty falling asleep or staying asleep, often associated with complications, such as fatigue, sleepiness, etc. Insomnia may cause disruptions in daytime physical and mental abilities. Orexins or hypocretins are the neuropeptides secreted from the lateral hypothalamus and play a major role in the sleep-wake cycle through a complex interplay between wake-promoting and sleep-promoting neuronal systems. Orexin receptor antagonists (Orexants) are the new treatment options for insomnia disorder, narcolepsy, and other sleep disturbances. There are two classes of Orexants, namely those that bind selectively to a specific orexin receptor are selective orexin receptor antagonists (SORA), and the others that bind to both the orexin receptors are dual orexin receptor antagonists (DORA). The first DORA was almorexant but restricted in use and the other three approved DORAs, such as suvorexant, lemborexant, and daridorexant were approved by the FDA, and several other DORAs and SORAs are under various stages of discovery and clinical investigation. Among the labeled limitations, the currently approved Orexants are contraindicated in people with narcolepsy and are controlled substances owing to their misuse liability. The present review discussed the sleep-wake cycle, phases of a sleep cycle, orexins, and Orexants, and summarized the pharmacology of the three approved DORAs, a type of Orexants and their potential advantages and limitations of their use in pharmacotherapy of insomnia disorder.

SGLT2 Inhibitors and Finerenone: A friendly Duo in the Treatment of Diabetic Kidney Disease?

For decades, achieving glycemic control, target blood pressure, and renin-angiotensin-aldosterone system (RAAS) blockade remained to be the therapeutic interventions for retarding diabetic kidney disease (DKD) progression. The management of DKD showed major transformation when SGLT2 inhibitors were recommended to reduce the risk of progressive deterioration in estimated glomerular filtration rate (eGFR), end-stage renal disease (ESRD), and renal death following results of CREDENCE and DAPA-CKD trials. Despite currently available therapeutic approaches, the risk of cardiac death, progression to ESRD, and requirement of renal replacement therapy remains high. Finerenone is the newer potent selective nonsteroidal mineralocorticoid receptor antagonist (MRA) that showed reduction in primary composite renal and CV outcomes in FIDELIO-DKD and FIGARO-DKD studies, respectively. While SGLT2 inhibitors have direct effects on cellular and metabolic functions besides reduction in glomerular hyperfiltration, finerenone primarily inhibits mineralocorticoid pathway-dependent inflammation and fibrosis. The renal benefits of dapagliflozin in the DAPA-CKD trial were regardless of MRA, and likewise, the benefits of finerenone in FIDELIO and FIGARO studies were irrespective of SGLT2i. Moreover, the risk of serious hyperkalemia with MRA was significantly reduced by concomitant use of SGLT2 inhibitors, making this combination a safer choice. Even though available data support the fact that this duo possibly has distinct as well as complementary mechanisms in protecting renal and cardiac functions, strong evidence to recommend routine use of the combination of SGLT2 inhibitors and MRA in DKD is currently lacking. However, the results of the ongoing CONFIDENCE study evaluating superiority of dual therapy of empagliflozin and finerenone will be worthwhile to understand the benefits of this friendly duo.