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Biochemical Pharmacology Jun 2024β2-adrenergic receptor (β2AR) agonists are the clinical gold standard for treatment and prophylaxis of airway constriction in pulmonary obstructive diseases such as... (Review)
Review
β2-adrenergic receptor (β2AR) agonists are the clinical gold standard for treatment and prophylaxis of airway constriction in pulmonary obstructive diseases such as asthma and COPD. Inhaled β2-agonists elicit rapid bronchorelaxation of the airway smooth muscle, yet, clinical tachyphylaxis to this response can occur over repeated and chronic use, which reduces the bronchodilatory effectiveness. Several mechanisms have been proposed to impart β2-agonist tachyphylaxis, most notably β2AR desensitization. However, airway tissue is known to be highly oxidative, particularly in obstructive disease states where reactive oxygen species (ROS) generation is upregulated and ROS degradation is suboptimal yielding a large oxidative burden. Recent evidence demonstrates that β2AR can regulate ROS generation and that ROS can post-translationally alter β2AR cysteine residues via oxidation, leading to distinct functional receptor outcomes. Herein, we discuss the growing evidence for β2AR mediated ROS generation in airway cells and the role of ROS in regulating β2AR via cysteine-oxidation of the receptor. Given the functional consequence of the β2AR-ROS signaling axis in the airways, we also discuss the potential role of ROS in mediating β2-agonist tachyphylaxis.
PubMed: 38945277
DOI: 10.1016/j.bcp.2024.116403 -
Journal of Chemical Theory and... Jun 2024The optimal interaction of drugs with plasma membranes and membranes of subcellular organelles is a prerequisite for desirable pharmacology. Importantly, for drugs...
Application of Generative Artificial Intelligence in Predicting Membrane Partitioning of Drugs: Combining Denoising Diffusion Probabilistic Models and MD Simulations Reduces the Computational Cost to One-Third.
The optimal interaction of drugs with plasma membranes and membranes of subcellular organelles is a prerequisite for desirable pharmacology. Importantly, for drugs targeting the transmembrane lipid-facing sites of integral membrane proteins, the relative affinity of a drug to the bilayer lipids compared to the surrounding aqueous phase affects the partitioning, access, and binding of the drug to the target site. Molecular dynamics (MD) simulations, including enhanced sampling techniques such as steered MD, umbrella sampling (US), and metadynamics, offer valuable insights into the interactions of drugs with the membrane lipids and water in atomistic detail. However, these methods are computationally prohibitive for the high-throughput screening of drug candidates. This study shows that applying denoising diffusion probabilistic models (DDPMs), a generative AI method, to US simulation data reduces the computational cost significantly. Specifically, the models used only partial (one-third) data from the US simulations and reproduced the complete potential of mean force (PMF) profiles for three FDA-approved drugs (β2-adrenergic agonists) and ∼20 biologically relevant chemicals with known experimentally characterized bilayer locations. Intriguingly, the model can predict the solvation-free energies for partitioning and crossing the bilayer, preferred bilayer locations (low-energy well), and orientations of the ligands with high accuracy. The results indicate that DDPMs can be used to characterize the complete membrane partitioning profile of drug molecules using fewer umbrella sampling simulations at select positions along the bilayer normal (-axis), irrespective of their amphiphilic-lipophilic-cephalophilic characteristics.
PubMed: 38942732
DOI: 10.1021/acs.jctc.4c00315 -
European Journal of Psychotraumatology 2024Clonidine is a centrally acting anti-adrenergic agent that may have applications in post-traumatic stress disorder (PTSD), particularly for sleep. In this systematic... (Review)
Review
Clonidine is a centrally acting anti-adrenergic agent that may have applications in post-traumatic stress disorder (PTSD), particularly for sleep. In this systematic review, we aimed to summarize the effect of clonidine on sleep quality and duration, nightmares, and PTSD symptom severity in adults with PTSD. PubMed (Medline), Embase, PsycINFO, CINAHL, and clinicaltrials.gov were searched up to April 2023. Studies on clonidine use in adult PTSD patients reporting data on the effect on sleep, nightmares, and PTSD symptoms were included. A narrative summary and a meta-analysis of the study findings are presented. Ten reports, accounting for = 569 patients with PTSD (145 on clonidine and 436 controls), were included in the final selection. There were four case reports, four observational studies, one non-blind clinical trial, and one crossover randomized controlled trial (RCT). Median clonidine dose was 0.15 mg/day (range: 0.1-0.5 mg/day). Median follow-up time was 31 days (range: 3 days to 19 months). The quality of the evidence was rated from very low to low. There was marked between-study heterogeneity and low power in the individual studies, but many reported improved sleep quality, nightmare reduction, and improvement of PTSD symptoms for patients treated with clonidine. Meta-analysis was only possible for two studies reporting the effect of clonidine on nightmares, and showed no difference from the comparator (i.e. prazosin or terazosin) (odds ratio: 1.16; 95% confidence interval: 0.66 to 2.05), potentially pointing towards non-inferiority between these medications. Future research, such as well-powered RCTs, is needed to identify the efficacy in the lower dose range and the most suitable treatment group, and to obtain good evidence on the effects of clonidine in the treatment of sleep disorders related to PTSD.
Topics: Clonidine; Humans; Stress Disorders, Post-Traumatic; Dreams; Sleep Quality; Adrenergic alpha-2 Receptor Agonists
PubMed: 38941125
DOI: 10.1080/20008066.2024.2366049 -
Journal of Immunology (Baltimore, Md. :... Jun 2024Catecholamines binding to α- and β-adrenergic receptors on immune cells have recently been shown to play an important role in regulating immune responses. Although...
Catecholamines binding to α- and β-adrenergic receptors on immune cells have recently been shown to play an important role in regulating immune responses. Although α2-adrenergic receptors are known to modulate the immune response in different ways, the therapeutic exploration of their utility has been limited by the lack of agonists selective for the three α2-adrenergic subtypes. We report in this study the identification of the agonist AGN-762, which activates α2B- and α2C-adrenergic subtypes, but not the α2A subtype. We show that AGN-762 reduced clinical disease in an experimental autoimmune encephalitis model of autoimmune disease via direct or indirect effects on T regulatory cells. The activity of AGN-762 was abrogated by depletion of T regulatory cells, which express the α2B-adrenergic receptor. Furthermore, a drug-induced shift to an anti-inflammatory phenotype was demonstrated in immune cells in the spleen of drug-treated experimental autoimmune encephalitis mice. AGN-762 does not display sedative and cardiovascular side effects associated with α2A subtype agonists. Immune modulation by selective α2-adrenergic agonists represents a novel, to our knowledge, approach for treating autoimmune disease.
PubMed: 38940628
DOI: 10.4049/jimmunol.2300893 -
International Archives of Allergy and... Jun 2024Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the...
Importance of IgE-Induced Unique Plasma Leakage in the Skin for Urticaria-Like Symptoms in an Anaphylaxis-Dependent Spotted Distribution of Immune Complex in Skin (ASDIS) Mouse Model.
INTRODUCTION
Allergic diseases, such as anaphylaxis and urticaria, pose significant health concerns. The quest for improved prognostic outcomes in these diseases necessitates the exploration of novel therapeutic avenues. To address this need, we have developed a novel mouse model of anaphylaxis, denoted as anaphylaxis-dependent spotted distribution of immune complex in skin (ASDIS). ASDIS manifests as distinct dotted symptoms in the skin, detectable through in vivo imaging, resembling urticarial symptoms. In this study, we investigated the potential underlying mechanisms giving rise to these dotted symptoms, exploring the role of vascular permeability and characterizing the ASDIS model as a new urticaria model.
METHODS
We employed haired and hairless HR mice (BALB/c background) and hairless HR-1 mice (a commercially available hairless strain with an unidentified genetic background). ASDIS was induced by the simultaneous intravenous injection of anti-ovalbumin IgE and fluorescein isothiocyanate (FITC)-ovalbumin, along with Evans blue - a recognized vascular permeability indicator. Anaphylaxis and scratching behavior were monitored through rectal temperature decrease and optical observation, respectively. Histamine, platelet-activating factor, and compound 48/80 were injected with or without FITC-ovalbumin for comparative analysis. The effects of an α1 adrenergic receptor agonist applied to the skin were also examined.
RESULTS
In hairless mice, the simultaneous injection of histamine, compound 48/80, or IgE with FITC-ovalbumin induced comparable rectal temperature decreases and vascular permeability. However, only the combination of FITC-ovalbumin and IgE triggered ASDIS, specifically the dotted urticaria-like symptom. Evans blue visualization and optical observation of dotted swelling confirmed that the vascular permeability mediated the phenomenon. Hairless mice exhibited a more pronounced temperature decrease than their haired counterparts when exposed to histamine, platelet-activating factor, compound 48/80, and IgE with FITC-ovalbumin. The application of an α1 adrenergic receptor agonist to the skin attenuated the topical urticaria-like symptom.
CONCLUSION
Our experiments revealed four findings. The first is that ASDIS mirrors urticaria-like symptoms resulting from increased vascular permeability, akin to human urticaria. The second finding is that the development of dotted symptoms involves an IgE-induced, yet unidentified, mechanism not triggered by histamine or compound 48/80 alone. The third finding highlights the heightened susceptibility of hairless mice to ASDIS induction. The fourth finding demonstrates that the inhibition of ASDIS by the topical application of an α1 adrenergic receptor agonist hints at a potential anti-urticarial application for this vasoconstrictor. Further elucidation of these unidentified IgE-dependent mechanisms and the specific generation of dotted symptoms by IgE-immune complexes could provide novel insights into allergic response processes and therapeutic interventions for these conditions.
PubMed: 38934152
DOI: 10.1159/000539215 -
Pharmaceuticals (Basel, Switzerland) Jun 2024Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances... (Review)
Review
Accidental poisonings by ingesting conjunctival fluid mixed with eye drops commonly involve alpha-2 adrenergic receptor agonists and tetrahydrozoline. These substances are recognized in commonly reported ingestions. Victims of all ages, otherwise in good health, often present as pale and lethargic to the emergency department (ED) after unintentionally ingesting topical eye medication. While eye drop poisoning cases in childhood include accidents during the play and poisonings in adults mean either suicide attempts or side effects caused by the systemic absorption of the substance, fluid of the ocular surface is a risk to all age groups. With this in mind, this study aimed to summarize data in the literature on tetrahydrozoline and alpha-2 adrenergic receptor agonists as dangerous medications, even when administered in low-bioavailability forms, such as eye drops. With this aim, a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-compliant systematic review of relevant studies was conducted. A search of PubMed, Scopus, Web of Science, and EBSCOhost yielded nine studies that met the rigorous inclusion criteria. The primary studies were subject to a meta-analysis once a quality appraisal of the studies and a narrative synthesis of the extracted data had been conducted. The author hopes that this information will provide observations that will lead to better designs for over-the-counter eye drops, off-label drug usage policies, and parental attention.
PubMed: 38931425
DOI: 10.3390/ph17060758 -
International Journal of Molecular... Jun 2024The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically,...
Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation-The Role of the Noradrenergic Transmission in the Basolateral Amygdala.
The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)-two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.
Topics: Animals; Memory Consolidation; Basolateral Nuclear Complex; Male; Rats; Odorants; Norepinephrine; Hippocampus; Emotions; Rats, Wistar; Cyclic AMP Response Element-Binding Protein; Propranolol
PubMed: 38928281
DOI: 10.3390/ijms25126576 -
Biomedicines May 2024Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30%...
Single and Combined Effects of Cannabigerol (CBG) and Cannabidiol (CBD) in Mouse Models of Oxaliplatin-Associated Mechanical Sensitivity, Opioid Antinociception, and Naloxone-Precipitated Opioid Withdrawal.
Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients, with estimates of at least 30% of patients experiencing persistent neuropathy for months or years after treatment cessation. An emerging potential intervention for the treatment of CIPN is cannabinoid-based pharmacotherapies. We have previously demonstrated that treatment with the psychoactive CB1/CB2 cannabinoid receptor agonist Δ-tetrahydrocannabinol (Δ-THC) or the non-psychoactive, minor phytocannabinoid cannabidiol (CBD) can attenuate paclitaxel-induced mechanical sensitivity in a mouse model of CIPN. We then showed that the two compounds acted synergically when co-administered in the model, giving credence to the so-called entourage effect. We and others have also demonstrated that CBD can attenuate several opioid-associated behaviors. Most recently, it was reported that another minor cannabinoid, cannabigerol (CBG), attenuated cisplatin-associated mechanical sensitivity in mice. Therefore, the goals of the present set of experiments were to determine the single and combined effects of cannabigerol (CBG) and cannabidiol (CBD) in oxaliplatin-associated mechanical sensitivity, naloxone-precipitated morphine withdrawal, and acute morphine antinociception in male C57BL/6 mice. Results demonstrated that CBG reversed oxaliplatin-associated mechanical sensitivity only under select dosing conditions, and interactive effects with CBD were sub-additive or synergistic depending upon dosing conditions too. Pretreatment with a selective α2-adrenergic, CB1, or CB2 receptor selective antagonist significantly attenuated the effect of CBG. CBG and CBD decreased naloxone-precipitated jumping behavior alone and acted synergistically in combination, while CBG attenuated the acute antinociceptive effects of morphine and CBD. Taken together, CBG may have therapeutic effects like CBD as demonstrated in rodent models, and its interactive effects with opioids or other phytocannabinoids should continue to be characterized.
PubMed: 38927352
DOI: 10.3390/biomedicines12061145 -
Journal of Chromatography. B,... Jun 2024Cortex Morin Radicis (CMR) is the dried root bark of Morus alba. L. It has a variety of effects such as antibacterial, anti-tumour, treatment of cardiovascular diseases...
Screening for promising multi-target bioactive components from Cortex Mori Radicis for the treatment of chronic cor pulmonale based on immobilized beta-adrenergic receptor and beta-adrenergic receptor chromatography.
Cortex Morin Radicis (CMR) is the dried root bark of Morus alba. L. It has a variety of effects such as antibacterial, anti-tumour, treatment of cardiovascular diseases or upper respiratory tract disease and so on. The pursuit for drugs selected from Cortex Mori Radicis having improved therapeutic efficacy necessitates increasing research on new assays for screening bioactive compounds with multi-targets. In this work, we applied immobilized β-AR and β-AR as the stationary phase in chromatographic column to screen bioactive compounds from Cortex Morin Radicis. Specific ligands of the two receptors (e.g. esmolol, metoprolol, atenolol, salbutamol, methoxyphenamine, tulobuterol and clorprenaline) were utilized to characterize the specificity and bioactivity of the columns. We used high performance affinity chromatography coupled with ESI-MS to screen targeted compounds of Cortex Morin Radicis. By zonal elution, we identified morin as a bioactive compound simultaneously binding to β-AR and β-AR. The compound exhibited the association constants of 3.10 × 10 and 2.60 × 10 M on the β-AR and β-AR column. On these sites, the dissociation rate constants were calculated to be 0.131 and 0.097 s. Molecular docking indicated that the binding of morin to the two receptors occurred on Asp200, Asp121, and Val122 of β-AR, Asn312, Thr110, Asp113, Tyr316, Gly90, Phe193, Ile309, and Trp109 of β-AR. Likewise, mulberroside C was identified as the bioactive compound binding to β-AR. The association constants and dissociation rate constants were calculated to be 1.08 × 10 M and 0.900 s. Molecular docking also indicated that mulberroside C could bind to β-AR receptor on its agonist site. Taking together, we demonstrated that the chromatographic strategy to identify bioactive natural products based on the β-AR and β-AR immobilization, has potential for screening bioactive compounds with multi-targets from complex matrices including traditional Chinese medicines.
PubMed: 38917653
DOI: 10.1016/j.jchromb.2024.124175 -
Science Signaling Jun 2024The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here,...
The stabilization of different active conformations of G protein-coupled receptors is thought to underlie the varying efficacies of biased and balanced agonists. Here, profiling the activation of signal transducers by angiotensin II type 1 receptor (ATR) agonists revealed that the extent and kinetics of β-arrestin binding exhibited substantial ligand-dependent differences, which were lost when receptor internalization was inhibited. When ATR endocytosis was prevented, even weak partial agonists of the β-arrestin pathway acted as full or near-full agonists, suggesting that receptor conformation did not exclusively determine β-arrestin recruitment. The ligand-dependent variance in β-arrestin translocation was much larger at endosomes than at the plasma membrane, showing that ligand efficacy in the β-arrestin pathway was spatiotemporally determined. Experimental investigations and mathematical modeling demonstrated how multiple factors concurrently shaped the effects of agonists on endosomal receptor-β-arrestin binding and thus determined the extent of functional selectivity. Ligand dissociation rate and G protein activity had particularly strong, internalization-dependent effects on the receptor-β-arrestin interaction. We also showed that endocytosis regulated the agonist efficacies of two other receptors with sustained β-arrestin binding: the V vasopressin receptor and a mutant β-adrenergic receptor. In the absence of endocytosis, the agonist-dependent variance in β-arrestin2 binding was markedly diminished. Our results suggest that endocytosis determines the spatiotemporal bias in GPCR signaling and can aid in the development of more efficacious, functionally selective compounds.
Topics: Endocytosis; Humans; Signal Transduction; Receptor, Angiotensin, Type 1; beta-Arrestins; HEK293 Cells; Receptors, Vasopressin; Receptors, Adrenergic, beta-2; Endosomes; Receptors, G-Protein-Coupled; Animals; Ligands; Protein Binding; Protein Transport
PubMed: 38917219
DOI: 10.1126/scisignal.adi0934