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1
Otto-Hanson, L. K., Z. Grabau, C. Rosen, C. E. Salomon, and L. L. Kinkel. "Pathogen Variation and Urea Influence Selection and Success of Streptomyces Mixtures in Biological Control." Phytopathology® 103, no. 1 (January 2013): 34–42. http://dx.doi.org/10.1094/phyto-06-12-0129-r.
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Success in biological control of plant diseases remains inconsistent in the field. A collection of well-characterized Streptomyces antagonists (n = 19 isolates) was tested for their capacities to inhibit pathogenic Streptomyces scabies (n = 15 isolates). There was significant variation among antagonists in ability to inhibit pathogen isolates and among pathogens in their susceptibility to inhibition. Only one antagonist could inhibit all pathogens, and antagonist–pathogen interactions were highly specific, highlighting the limitations of single-strain inoculum in biological control. However, the collection of pathogens could be inhibited by several combinations of antagonists, suggesting the potential for successful antagonist mixtures. Urea generally increased effectiveness of antagonists at inhibiting pathogens in vitro (increased mean inhibition zones) but its specific effects varied among antagonist–pathogen combinations. In greenhouse trials, urea enhanced the effectiveness of antagonist mixtures relative to individual antagonists in controlling potato scab. Although antagonist mixtures were frequently antagonistic in the absence of urea, all n= 2 and n = 3 antagonist–isolate combinations were synergistic in the presence of urea. This work provides insights into the efficacy of single- versus multiple-strain inocula in biological control and on the potential for nutrients to influence mixture success.
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Dilger, James P., Ana Maria Vidal, Man Liu, Claire Mettewie, Takahiro Suzuki, Anh Pham, and Deeptankar Demazumder. "Roles of Amino Acids and Subunits in Determining the Inhibition of Nicotinic Acetylcholine Receptors by Competitive Antagonists." Anesthesiology 106, no. 6 (June 1, 2007): 1186–95. http://dx.doi.org/10.1097/01.anes.0000267602.94516.7f.
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Background Binding sites for agonists and competitive antagonists (nondepolarizing neuromuscular blocking agents) are located at the alpha-delta and alpha-epsilon subunit interfaces of adult nicotinic acetylcholine receptors. Most information about the amino acids that participate in antagonist binding comes from binding studies with (+)-tubocurarine and metocurine. These bind selectively to the alpha-epsilon interface but are differentially sensitive to mutations. To test the generality of this observation, the authors measured current inhibition by five competitive antagonists on wild-type and mutant acetylcholine receptors. Methods HEK293 cells were transfected with wild-type or mutant (alphaY198F, epsilonD59A, epsilonD59N, epsilonD173A, epsilonD173N, deltaD180K) mouse muscle acetylcholine receptor complementary DNA. Outside-out patches were excised and perfused with acetylcholine in the absence and presence of antagonist. Concentration-response curves were constructed to determine antagonist IC50. An antagonist-removal protocol was used to determine dissociation and association rates. Results Effects of mutations were antagonist specific. alphaY198F decreased the IC50 of (+)-tubocurarine 10-fold, increased the IC50 of vecuronium 5-fold, and had smaller effects on other antagonists. (+)-Tubocurarine was the most sensitive antagonist to epsilonD173 mutations. epsilonD59 mutations had large effects on metocurine and cisatracurium. deltaD180K decreased inhibition by pancuronium, vecuronium, and cisatracurium. Inhibition by these antagonists was increased for receptors containing two delta subunits but no epsilon subunit. Differences in IC50 arose from differences in both dissociation and association rates. Conclusion Competitive antagonists exhibited different patterns of sensitivity to mutations. Except for pancuronium, the antagonists were sensitive to mutations at the alpha-epsilon interface. Pancuronium, vecuronium, and cisatracurium were selective for the alpha-delta interface. This suggests the possibility of synergistic inhibition by pairs of antagonists.
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Presti, M. E., and J. D. Gardner. "Receptor antagonists for gastrointestinal peptides." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 3 (March 1, 1993): G399—G406. http://dx.doi.org/10.1152/ajpgi.1993.264.3.g399.
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Receptors for gastrointestinal peptides are all G protein-coupled receptors. Since the discovery that dibutyryl guanosine 3',5'-cyclic monophosphate was a cholecystokinin-receptor antagonist, a variety of receptor antagonists have been developed for a number of different gastrointestinal peptides. These antagonists have been useful in classifying receptors for gastrointestinal peptides and in elucidating complex regulation of gastrointestinal function. Some antagonists also have therapeutic potential. Based on the receptors with which they interact, gastrointestinal peptides can be grouped into families, and, in general, a given receptor antagonist is specific for a given family. This review covers the different families of gastrointestinal peptides and the major antagonists that exist for each family.
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Robben, J. H., M. Sze, N. V. A. M. Knoers, and P. M. T. Deen. "Functional rescue of vasopressin V2 receptor mutants in MDCK cells by pharmacochaperones: relevance to therapy of nephrogenic diabetes insipidus." American Journal of Physiology-Renal Physiology 292, no. 1 (January 2007): F253—F260. http://dx.doi.org/10.1152/ajprenal.00247.2006.
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Intracellular retention of a functional vasopressin V2 receptor (V2R) is a major cause of congenital nephrogenic diabetes insipidus (NDI) and rescue of V2R mutants by nonpeptide antagonists may restore their basolateral membrane (BM) localization and function. However, the criteria for efficient functional rescue of G protein-coupled receptor (GPCR) mutants at clinically feasible antagonist concentrations are unknown. We found that the four nonpeptide antagonists SR49059, OPC31260 , OPC41061 , and SR121463B induced maturation and rescued the BM expression of eight of nine different V2R mutants, stably expressed in physiologically relevant polarized cells. The extent of maturation and rescued BM expression correlated with the antagonists' concentration and affinity for the V2R. Displacement of the antagonists by AVP and subsequent cAMP generation inversely correlated with the antagonists' affinities for the V2R but is partially influenced by antagonist-specific aspects. Despite limited increases in maturation and cell-surface expression of V2R mutants, the low-affinity SR49059 optimally induced functional rescue at high concentrations, due to its easy displacement by vasopressin. At clinically feasible antagonist concentrations, however, only the high-affinity antagonists OPC31260 and OPC41061 induced functional rescue, as at these concentrations the extent of BM expression became limited. In conclusion, functional rescue of mutant V2Rs at clinically feasible concentrations is most effective with high-affinity antagonists. As OPC31260 and OPC41061 are clinically safe, they are promising candidates to relieve NDI. Moreover, as numerous other diseases are caused by endoplasmic reticulum-retained GPCRs for which cell-permeable antagonists become available, our finding that high-affinity antagonists are superior is anticipated to be important for pharmacotherapy development of these diseases.
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Okada, H., H. Suzuki, Y. Kanno, Y. Yamamura, and T. Saruta. "Chronic and selective vasopressin blockade in spontaneously hypertensive rats." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 267, no. 6 (December 1, 1994): R1467—R1471. http://dx.doi.org/10.1152/ajpregu.1994.267.6.r1467.
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Chronic effects of orally available, nonpeptide vasopressin V1 and V2 receptor antagonists on conscious spontaneously hypertensive rats (SHR) were investigated. SHR and Wistar rats were divided into four groups, groups S-1 to S-4 and W-1 to W-4, respectively. Groups S-1 and W-1 were untreated as control. Groups S-2 and W-2 were treated with V1 antagonist, groups S-3 and W-3 received V2 antagonist, and groups S-4 and W-4 were treated with both of V1 and V2 antagonists. V1 and/or V2 antagonists did not affect degree of blood pressure of W-2, W-3, and W-4 rats, and V1 antagonist, alone or combined with V2 antagonist, slightly reduced increases in blood pressure of S-2 and S-4 rats without significance. However, V2 antagonist induced significantly massive and hyposmolar urine in W-3 rats compared with that in S-3 rats. In conclusion, in SHR, circulating vasopressin contributes to increases in blood pressure via either V1 or V2 receptors less than expected from previous studies with antibodies or peptide antagonists.
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Barth, Francis, and Murielle Rinaldi-Carmona. "The Development of Cannabinoid Antagonists." Current Medicinal Chemistry 6, no. 8 (August 1999): 745–55. http://dx.doi.org/10.2174/0929867306666220401143808.
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The discovery of two distinct cannabinoid receptors (CB1 and C B 2 ) in the early 1990's has revived the research on cannabinoid antagonists. While the search for antagonists based on the structure of agonists (classical cannabinoids or aminoalkylindoles) appeared rather disappointing, the first potent cannabinoid antagonists were developed in a new chemical series: the diarylpyrazoles. Since its discovery in 1994, the selective CB1 antagonist SR 141716 has become a major pharmacological tool to elucidate the physiological role of the CB 1 cannabinoid receptor and its endogenous ligand. The selective CB2 antagonist SR 144528 is expected to play the same role for the CB2 receptors, while the recent development of cannabinoid antagonists belonging to other chemical series illustrates the interest of these compounds which are now considered as interesting therapeutic targets by many pharmaceutical companies.
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Schulz, Ashley N., Rima D. Lucardi, and Travis D. Marsico. "Successful Invasions and Failed Biocontrol: The Role of Antagonistic Species Interactions." BioScience 69, no. 9 (August 7, 2019): 711–24. http://dx.doi.org/10.1093/biosci/biz075.
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Abstract Understanding the successes and failures of nonnative species remains challenging. In recent decades, researchers have developed the enemy release hypothesis and other antagonist hypotheses, which posit that nonnative species either fail or succeed in a novel range because of the presence or absence of antagonists. The premise of classical biological control of invasive species is that top-down control works. We identify twelve existing hypotheses that address the roles that antagonists from many trophic levels play during plant and insect invasions in natural environments. We outline a unifying framework of antagonist hypotheses to simplify the relatedness among the hypotheses, incorporate the role of top-down and bottom-up influences on nonnative species, and encourage expansion of experimental assessments of antagonist hypotheses to include belowground and fourth trophic level antagonists. A mechanistic understanding of antagonists and their impacts on nonnative species is critical in a changing world.
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Bödder, Johanna, Leanne M. Kok, Jonathan A. Fauerbach, Georgina Flórez-Grau, and I. Jolanda M. de Vries. "Tailored PGE2 Immunomodulation of moDCs by Nano-Encapsulated EP2/EP4 Antagonists." International Journal of Molecular Sciences 24, no. 2 (January 11, 2023): 1392. http://dx.doi.org/10.3390/ijms24021392.
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Prostaglandin E2 (PGE2) is an important maturation mediator for dendritic cells (DCs). However, increased PGE2 levels in the tumor exert immunosuppressive effects on DCs by signaling through two E-Prostanoid (EP) receptors: EP2 and EP4. Blocking EP-receptor signaling of PGE2 with antagonists is currently being investigated for clinical applications to enhance anti-tumor immunity. In this study, we investigated a new delivery approach by encapsulating EP2/EP4 antagonists in polymeric nanoparticles. The nanoparticles were characterized for size, antagonist loading, and release. The efficacy of the encapsulated antagonists to block PGE2 signaling was analyzed using monocyte-derived DCs (moDCs). The obtained nanoparticles were sized between 210 and 260 nm. The encapsulation efficacy of the EP2/EP4 antagonists was 20% and 17%, respectively, and was further increased with the co-encapsulation of both antagonists. The treatment of moDCs with co-encapsulation EP2/EP4 antagonists prevented PGE2-induced co-stimulatory marker expression. Even though both antagonists showed a burst release within 15 min at 37 °C, the nanoparticles executed the immunomodulatory effects on moDCs. In summary, we demonstrate the functionality of EP2/EP4 antagonist-loaded nanoparticles to overcome PGE2 modulation of moDCs.
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Geling, Olga, and Hans-Georg Eichler. "Should 5-Hydroxytryptamine-3 Receptor Antagonists Be Administered Beyond 24 Hours After Chemotherapy to Prevent Delayed Emesis? Systematic Re-Evaluation of Clinical Evidence and Drug Cost Implications." Journal of Clinical Oncology 23, no. 6 (February 20, 2005): 1289–94. http://dx.doi.org/10.1200/jco.2005.04.022.
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Purpose 5-Hydroxytryptamine-3 receptor antagonists (5-HT3 antagonists) are effective for preventing acute chemotherapy-induced emesis but the benefits of continuing administration of these agents beyond 24 hours after chemotherapy (delayed emesis) remain unclear. The purpose of this study was to provide estimates of clinical efficacy and drug acquisition cost associated with administering 5-HT3 antagonists beyond 24 hours, as monotherapy or as added to dexamethasone. Methods This analysis is based on the Cancer Care Ontario Practice Guidelines Initiative meta-analysis of the efficacy of 5-HT3 antagonists. Results from the clinical trials covered in that meta-analysis were reanalyzed to provide estimates of absolute risk reductions (ARR) and numbers needed to treat (NNT) for 5-HT3 antagonists, as monotherapy or as adjunct treatment. Numbers of 5-HT3 antagonist unit doses per successfully treated patient were also calculated. Results Five studies (comprising 1,716 assessable patients) compared a 5-HT3 antagonist with placebo; five studies (2,240 patients) compared a combination of a 5-HT3 antagonist and dexamethasone with dexamethasone monotherapy. ARR for monotherapy was only 8.2% (95% CI, 3.0% to 13.4%). On average, 74 5-HT3 antagonist doses must be administered to 12 patients (NNT, 12.2; 95% CI, 7.5 to 33.4) not receiving dexamethasone to protect one patient from delayed emesis. In those patients receiving dexamethasone as standard antiemetic treatment in the delayed phase, the addition of a 5-HT3 antagonist did not significantly improve control of delayed emesis as compared with dexamethasone monotherapy (ARR, 2.6%; 95% CI, −0.6% to 5.8%). Conclusion Neither clinical evidence nor considerations of cost effectiveness justify using 5-HT3 antagonists beyond 24 hours after chemotherapy for prevention of delayed emesis.
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Varma, Daya R. "Ligand-independent negative chronotropic responses of rat and mouse right atria to β-adrenoceptor antagonists." Canadian Journal of Physiology and Pharmacology 77, no. 12 (November 15, 1999): 943–49. http://dx.doi.org/10.1139/y99-099.
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Negative chronotropic effects of β-adrenoceptor (βAR) antagonists on right atria from reserpine-treated rats and mice were determined as a test of their inverse agonist activities. β2AR antagonist ICI-118,551 and nonselective βAR antagonists alprenolol, propranolol, and timolol produced negative chronotropic effects. In contrast, nonselective βAR antagonists pindolol and nadolol as well as β1AR-selective antagonists atenolol, acebutolol, and metoprolol did not cause a significant decrease in atrial rates. The neutral antagonist pindolol but not the inverse agonist alprenolol inhibited the negative chronotropic activities of ICI-118,551. Isoprenaline, salbutamol, and noradrenaline produced positive chronotropic effects; the chronotropic effects of isoprenaline and salbutamol but not of noradrenaline were antagonized by ICI-118,551. It is concluded that both β1AR and β2AR mediate positive chronotropic effects of catecholamines on rat and mouse atria but only β2AR are constitutively active.Key words: inverse agonism, ICI-118,551, β1 adrenoceptor-selective antagonists, chronotropic responses, catecholamines.
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Selvaraj, Divakar, Sivaram Hariharan, and Ramanathan Muthiah. "Identification of Pharmacophore for Wild and T877A Mutant Androgen Receptor Antagonist." International Journal of Quantitative Structure-Property Relationships 2, no. 2 (July 2017): 47–61. http://dx.doi.org/10.4018/ijqspr.2017070105.
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Androgen increases the proliferation of prostate cancer cells by activating the androgen receptor (AR). AR antagonists block the androgen mediated proliferation and are used to treat prostate cancer. Antagonist resistance occurs due to the expression of mutations in AR. One particular mutation, T877A, was frequently expressed in relapsed patients. Presently, there is no antagonist in the market without the problem of resistance developing over the period of treatment. A plausible reason for this shortcoming could be the lack of designing because of the unavailability of AR-crystal structure in antagonist bound conformation. Hence, 3D-QSAR becomes a major tool in identification of novel AR antagonists. Three models, ADDHRR.295, AHHRR.266, and AHRR.63 were designed for wild type, T877A mutant, and full (active at both wild and mutant types) AR antagonists respectively. There is a major difference in the angles and lengths of the pharmacophore site points among the 3D-QSAR models. The generated pharmacophore for full antagonists was then used for screening the SPECS database with filters for identifying hits.
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Tay, Apple Hui Min, Rubén Prieto-Díaz, Shiyong Neo, Le Tong, Xinsong Chen, Valentina Carannante, Björn Önfelt, et al. "A2B adenosine receptor antagonists rescue lymphocyte activity in adenosine-producing patient-derived cancer models." Journal for ImmunoTherapy of Cancer 10, no. 5 (May 2022): e004592. http://dx.doi.org/10.1136/jitc-2022-004592.
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BackgroundAdenosine is a metabolite that suppresses antitumor immune response of T and NK cells via extracellular binding to the two subtypes of adenosine-2 receptors, A2ARs. While blockade of the A2AARs subtype effectively rescues lymphocyte activity, with four A2AAR antagonists currently in anticancer clinical trials, less is known for the therapeutic potential of the other A2BAR blockade within cancer immunotherapy. Recent studies suggest the formation of A2AAR/A2BAR dimers in tissues that coexpress the two receptor subtypes, where the A2BAR plays a dominant role, suggesting it as a promising target for cancer immunotherapy.MethodsWe report the synthesis and functional evaluation of five potent A2BAR antagonists and a dual A2AAR/A2BAR antagonist. The compounds were designed using previous pharmacological data assisted by modeling studies. Synthesis was developed using multicomponent approaches. Flow cytometry was used to evaluate the phenotype of T and NK cells on A2BAR antagonist treatment. Functional activity of T and NK cells was tested in patient-derived tumor spheroid models.ResultsWe provide data for six novel small molecules: five A2BAR selective antagonists and a dual A2AAR/A2BAR antagonist. The growth of patient-derived breast cancer spheroids is prevented when treated with A2BAR antagonists. To elucidate if this depends on increased lymphocyte activity, immune cells proliferation, and cytokine production, lymphocyte infiltration was evaluated and compared with the potent A2AAR antagonist AZD-4635. We find that A2BAR antagonists rescue T and NK cell proliferation, IFNγ and perforin production, and increase tumor infiltrating lymphocytes infiltration into tumor spheroids without altering the expression of adhesion molecules.ConclusionsOur results demonstrate that A2BAR is a promising target in immunotherapy, identifying ISAM-R56A as the most potent candidate for A2BAR blockade. Inhibition of A2BAR signaling restores T cell function and proliferation. Furthermore, A2BAR and dual A2AAR/A2BAR antagonists showed similar or better results than A2AAR antagonist AZD-4635 reinforcing the idea of dominant role of the A2BAR in the regulation of the immune system.
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Jacoby, David B., Bethany L. Yost, Thomas Elwood, and Allison D. Fryer. "Effects of neurokinin receptor antagonists in virus-infected airways." American Journal of Physiology-Lung Cellular and Molecular Physiology 279, no. 1 (July 1, 2000): L59—L65. http://dx.doi.org/10.1152/ajplung.2000.279.1.l59.
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We investigated the effects of a neurokinin-1 (NK1) receptor antagonist (SR-140333) and a NK2 receptor antagonist (SR-48968) on airway responsiveness and on the function of neuronal M2 muscarinic receptors, which normally inhibit vagal acetylcholine release, in guinea pigs infected with parainfluenza virus. Antagonists were given 1 h before infection and daily thereafter. Four days later, bronchoconstriction induced by either intravenous histamine (which is partly vagally mediated) or electrical stimulation of the vagus nerves was increased by viral infection compared with control. In addition, the ability of the muscarinic agonist pilocarpine to inhibit vagally induced bronchoconstriction was lost in virus-infected animals, demonstrating loss of neuronal M2 receptor function. Macrophage influx into the lungs was inhibited by pretreatment with both antagonists. However, only the NK1 receptor antagonist prevented M2 receptor dysfunction and inhibited hyperresponsiveness (measured as an increase in either vagally induced or histamine-induced bronchoconstriction). Thus virus-induced M2 receptor dysfunction and hyperresponsiveness are prevented by a NK1 receptor antagonist, but not by a NK2 receptor antagonist, whereas both antagonists had similar anti-inflammatory effects.
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Noman, Md Abdullah Al, Jillian L. Kyzer, Sanny S. W. Chung, Debra J. Wolgemuth, and Gunda I. Georg. "Retinoic acid receptor antagonists for male contraception: current status†." Biology of Reproduction 103, no. 2 (July 15, 2020): 390–99. http://dx.doi.org/10.1093/biolre/ioaa122.
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Abstract Retinoic acid receptor alpha (RARA), a nuclear receptor protein, has been validated as a target for male contraception by gene knockout studies and also pharmacologically using a pan-retinoic acid receptor antagonist. Retinoic acid receptor alpha activity is indispensable for the spermatogenic process, and therefore its antagonists have potential as male contraceptive agents. This review discusses the effects of systematic dosing regimen modifications of the orally bioavailable and reversible pan-antagonist BMS-189453 as well as studies with the alpha-selective antagonists BMS-189532 and BMS-189614 in a murine model. We also provide an overview of structure–activity studies of retinoic acid receptor alpha antagonists that provide insight for the design of novel alpha-selective ligands.
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Watanabe, Masaki, and Hiroki Kakuta. "Retinoid X Receptor Antagonists." International Journal of Molecular Sciences 19, no. 8 (August 10, 2018): 2354. http://dx.doi.org/10.3390/ijms19082354.
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Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clinical use. In this review, we present a brief overview of RXR structure, function, and target genes, and describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research.
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Sakkiah, Sugunadevi, Chandrabose Selvaraj, Wenjing Guo, Jie Liu, Weigong Ge, Tucker A. Patterson, and Huixiao Hong. "Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations." International Journal of Molecular Sciences 22, no. 17 (August 29, 2021): 9371. http://dx.doi.org/10.3390/ijms22179371.
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Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17β-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses.
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Rojas, C., M. Stathis, J. Alt, E. Rubenstein, S. Cantoreggi, S. Sebastiani, and B. Slusher. "Additional binding mechanism of palonosetron to the 5-HT3 receptor versus first generation 5-HT3 receptor antagonists." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 19583. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.19583.
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19583 Background: Palonosetron has a higher binding affinity and longer plasma half-life than first generation 5-HT3 receptor antagonists. Clinical trials have demonstrated that a single intravenous dose of palonosetron 0.25 mg provides better protection from chemotherapy-induced nausea and vomiting than other 5-HT3 receptor antagonists throughout the 5-day post-chemotherapy period. The purpose of this work is to determine differences in the molecular interactions of the antagonists with the receptor that could help explain the clinical efficacy differences. Methods: Molecular ligand-receptor relationships for commonly used 5-HT3 receptor antagonists were investigated. In particular, competitive vs. potential allosteric interactions between ondansetron, granisetron and palonosetron and the 5-HT3 receptor were examined. Binding experiments were carried out using each unlabeled antagonist in competition with [3H]-antagonist. Concentrations of [3H]-antagonists used in these experiments included the equilibrium dissociation constant (Ki) and several-fold Ki values in an effort to represent the probable concentrations of each antagonist at the receptor site in vivo. The inhibitory concentration of unlabeled antagonist needed to observe half maximal binding (IC50) as a function of [3H]-antagonist concentration was plotted for comparisons between ondansetron, granisetron and palonosetron. Results: A plot of the concentration of unlabeled antagonist needed to observe IC50 as a function of [3H]- antagonist concentration was linear when ondansetron and granisetron were in competition. On the other hand, when palonosetron was in competition with either granisetron or ondansetron the plot was curvilinear in each case. Conclusions: These results indicate that palonosetron exhibits both competitive and allosteric interactions with the 5-HT3 receptor, in contrast to ondansetron and granisetron which display strictly competitive antagonism. As allosteric interactions may induce changes in the receptor conformation, we can speculate that palonosetron's dual action on the 5-HT3-receptor could induce amplification of its inhibitory effect at the primary receptor binding site. No significant financial relationships to disclose.
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Lowe III, John A., and Stafford McLean. "Tachykinin Antagonists." Current Pharmaceutical Design 1, no. 3 (October 1995): 269–78. http://dx.doi.org/10.2174/1381612801666220918144023.
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The discovery of nonpeptide antagonists of the tachykinin peptides substance P, neurokinin A, and neurokinin B has greatly accelerated pharmacological characterization of the role of these peptides and their receptors (NK-1, NK-2, and NK-3) in the central nervous system (CNS). The extensive structural diversity of the nonpeptide tachykinin antagonists offers considerable potential for therapeutic agents targeting this system, and includes NK-1 antagonists such as: I. the quinuclidine amines (CP-96,345) and related ethers, 2. the piperidine amines (CP-99,994) and related ethers and acyclic variants, 3. the isoindolines such as RP 67,580 and RPR 100,893, 4. the 2-benzylpiperidines CGP-47,899 and CGP 49,823, 5. the peptide-derived FK-888, and 6. SR-140,333, as well as NK-2 antagonists such as SR-48,968, and GR-159,897, and NK-3 antagonists such as PD- 157,652 and SR-142,801. Important new pharmacological insights facilitated by these compounds indicate a role for tachykinin peptides in control of dopamine function in the CNS, emesis, pain, and neurogenic inflammation. These compounds have also enabled characterization of the nonpeptide antagonist binding site on the NK-1 receptor, providing insight on the mechanism of receptor antagonism to help in the design of new compounds. Hence the nonpeptide tachykinin antagonists continue to play an important role in characterizing biochemical, pharmacological, and potential therapeutic aspects of the tachykinin peptides.
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Fong, Tung Ming, Ruey-Ruey C. Huang, Hong Yu, Dennis Underwood, Margaret A. Cascieri, Catherine D. Strader, and Christopher J. Swain. "Mutational analysis of neurokinin receptor function." Canadian Journal of Physiology and Pharmacology 73, no. 7 (July 1, 1995): 860–65. http://dx.doi.org/10.1139/y95-118.
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The interactions of the NK1 receptor with peptide agonists or nonpeptide antagonists have been investigated by site-directed mutagenesis and computer modeling. At least 10 residues in the extracellular and transmembrane regions of the receptor are required for the binding of many peptide agonists. The C-terminal amide of peptide agonists is likely to be bound near Asn-85. Residues likely to be involved in the subsequent receptor activation include Glu-78 and Tyr-205. The binding site for nonpeptide antagonists can be defined by at least five residues in transmembrane helices 4–7, and primary contacts between key residues and quinuclidine antagonists have been assigned based on CP-96,345 and its analogs. Analyses of the wild-type and mutant NK1 and NK2 receptors, intact and truncated peptides, and various antagonists suggest that the agonist and antagonist binding sites overlap spatially, even though agonists and antagonists do not interact with the same set of residues on the receptor. Mapping the ligand binding site not only allows us to better understand the ligand–receptor interaction and antagonism but also leads to a refined three-dimensional model of the NK1 receptor.Key words: receptor, substance P, agonist, antagonist, mutagenesis.
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Marques-Matos, Cláudia, José Nuno Alves, João Pedro Marto, Joana Afonso Ribeiro, Ana Monteiro, José Araújo, Fernando Silva, et al. "POST-NOAC: Portuguese observational study of intracranial hemorrhage on non-vitamin K antagonist oral anticoagulants." International Journal of Stroke 12, no. 6 (December 1, 2016): 623–27. http://dx.doi.org/10.1177/1747493016681021.
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Background There is a lower reported incidence of intracranial hemorrhage with non-vitamin K antagonist oral anticoagulants compared with vitamin K antagonist. However, the functional outcome and mortality of intracranial hemorrhage patients were not assessed. Aims To compare the outcome of vitamin K antagonists- and non-vitamin K antagonist oral anticoagulants-related intracranial hemorrhage. Methods We included consecutive patients with acute non-traumatic intracranial hemorrhage on oral anticoagulation therapy admitted between January 2013 and June 2015 at four university hospitals. Clinical and demographic data were obtained from individual medical records. Intracranial hemorrhage was classified as intracerebral, extra-axial, or multifocal using brain computed tomography. Three-month functional outcome was assessed using the modified Rankin Scale. Results Among 246 patients included, 24 (9.8%) were anticoagulated with a non-vitamin K antagonist oral anticoagulants and 222 (90.2%) with a vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants patients were older (81.5 vs. 76 years, p = 0.048) and had intracerebral hemorrhage more often (83.3% vs. 63.1%, p = 0.048). We detected a non-significant trend for larger intracerebral hemorrhage volumes in vitamin K antagonists patients ( p = 0.368). Survival analysis adjusted for age, CHA2DS2VASc, HAS-BLED, and anticoagulation reversal revealed that non-vitamin K antagonist oral anticoagulants did not influence three-month mortality (hazard ratio (HR) = 0.83, 95% confidence interval (CI) = 0.39–1.80, p = 0.638). Multivariable ordinal regression for three-month functional outcome did not show a significant shift of modified Rankin Scale scores in non-vitamin K antagonist oral anticoagulants patients (odds ratio (OR) 1.26, 95%CI 0.55–2.87, p = 0.585). Conclusions We detected no significant differences in the three-month outcome between non-vitamin K antagonist oral anticoagulants- and vitamin K antagonists-associated intracranial hemorrhage, despite unavailability of non-vitamin K antagonist oral anticoagulants-specific reversal agents.
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Gnus, Jan, Albert Czerski, Stanisław Ferenc, Wojciech Zawadzki, Wojciech Witkiewicz, Agnieszka Rusiecka, Jolanta Bujok, Willy Hauzer, Maciej Janeczek, and Aleksander Chrószcz. "Role of α1-adrenergic receptor subtypes in contractility of the rabbit abdominal aorta in vitro." Acta Veterinaria Brno 82, no. 3 (2013): 331–36. http://dx.doi.org/10.2754/avb201382030331.
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Investigation of the effect of α1-adrenergic receptor subtypes on the contraction of the abdominal aorta will allow for more effective treatment of hypertension by use of selective antagonists. The aim of the study was to evaluate the participation of α1-adrenergic receptor subtypes in the contractility of the aortic smooth muscle cells in rabbits. The in vitro experiments were performed in isolated tissue preparations from 30 adult female New Zealand rabbits. The abdominal aortic sections were placed in organ bath chambers and contracted with increasing doses of non-selective α1-adrenergic receptor agonist phenylephrine without pre-incubation or after incubation in α1-adrenergic receptor subtype-selective or non-selective antagonists. Separate sections were incubated with increasing concentrations of antagonists. Phenylephrine caused maximal rise in arterial smooth muscle tone to 4.75 ± 0.47 mN. The most potent in blocking phenylephrine induced contraction was 5-metylurapidil (α1A-adrenergic receptor antagonist) followed by phentolamine and prazosin (non-selective α1-adrenergic receptor antagonists); BMY 7378 (α1D-adrenergic receptor antagonist), cyclazosin and L-765.314 (α1B-adrenergic receptor antagonists) were less effective. All antagonists, except BMY 7378 elicited relaxation of non-precontracted aorta in dose dependent manner. Our results indicate that postsynaptic α1A receptors are the most potent in producing rabbit abdominal aorta contraction, while α1B and α1D subtypes are less effective.
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Kask, Ants, Helgi B. Schiöth, Jaanus Harro, Jarl ES Wikberg, and Lembit Rägo. "Orexigenic effect of the melanocortin MC4 receptor antagonist HS014 is inhibited only partially by neuropeptide Y Y1 receptor selective antagonists." Canadian Journal of Physiology and Pharmacology 78, no. 2 (February 1, 2000): 143–49. http://dx.doi.org/10.1139/y99-124.
Full textAbstract:
Neuropeptide Y (NPY) and melanocortin (MC) peptides have opposite effects on food intake: NPY-like peptides and MC receptor antagonists stimulate feeding and increase body weight, whereas melanocortins and NPY antagonists inhibit food intake. In this study we tested whether the orexigenic effect of the selective MC4 receptor antagonist HS014 (1 nmol) could be inhibited by three different NPY antagonists, (R)-N2-(diphenylacetyl)-N-[(4-hydroxy-phenyl)methyl]- D-argininamide (BIBP3226), (R)-N-[[4-(aminocarbonylaminomethyl)-phenyl]methyl]-N2-(diphenylacetyl)-argininamide-trifluoroacetate (BIBO3304), and decapeptide [D-Tyr27,36D-Thr32]NPY27-36, after icv administration in freely feeding male rats. All three NPY receptor antagonists inhibited the orexigenic effects of HS014 partially and with markedly different potency. [D-Tyr27,36D-Thr32]NPY27-36 was active only in subconvulsive dose. The NPY Y1 selective antagonist BIBP3226 was more effective in inhibiting the effect of HS014 than BIBO3304 despite in vitro data indicating that BIBP3226 is about 10 times less potent than BIBO3304 at NPY Y1 receptor. An enantiomer of BIBO3304, BIBO3457, failed to inhibit HS014-induced feeding, indicating that the effects of BIBO3304 were stereoselective. These results suggest that stimulation of food intake caused by weakening of melanocortinergic tone at the MC4 receptor is partially but not exclusively related to NPY Y1 receptor activation.Key words: neuropeptide Y, NPY Y1 receptor antagonist, BIBO3304, BIBP3226, [D-Tyr27,36D-Thr32]NPY(27-36), 1229U91, food intake, MC4 receptor antagonist, HS014.
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Abujalala, Mohammed, and A. Nehir Özden. "Effects of Polishing versus Glazing on Dental Ceramic Wear: A Comparative In Vitro Study." Journal of Medical Imaging and Health Informatics 11, no. 1 (January 1, 2021): 73–79. http://dx.doi.org/10.1166/jmihi.2021.3271.
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This study analyzed the wear behavior caused by steatite antagonists to four dental ceramic materials, comparing this between two surface treatments: polishing and glazing. Methods: Thirty flat samples (10 × 8 × 2 mm) were prepared from each of four ceramics: IPS e. max CAD (IPS), GC Initial LiSi Press (LP), Vita Enamic (VE), and monolithic zirconia (MZ). Subgroups of samples were finished by polishing or glazing or neither (as controls). The samples were subjected to computer-controlled chewing simulation (240,000 cycles of 49 N at 1.6 Hz, with thermocycling at 5/55 C), with steatite balls as antagonists. The samples and antagonists were visualized before and after the test with a laser abrasion measurement system, a CAD/CAM scanner, and electron microscopy scanning, and the volumes lost from the tested samples and antagonists were analyzed. Results: For the MZ samples, the polished samples showed significantly less volume loss than the glazed samples (0.0200 mm3 vs. 0.0305 mm3; p =0.0001), whereas there was significantly greater antagonist volume loss (0.0365 mm3 vs. 0.0240 mm3; p = 0.011). There were no significant differences between the subgroups for IPS, VE, and LP, although antagonist volume losses were non-significantly greater with the glazed samples than with the polished samples. Conclusions: Polishing MZ had adverse effects on the corresponding antagonist wear. Glazed MZ showed the lowest antagonist wear.
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Nakanishi, T., A. Yamauchi, H. Nakahama, Y. Yamamura, Y. Yamada, Y. Orita, Y. Fujiwara, N. Uyeda, Y. Takamitsu, and M. Sugita. "Organic osmolytes in rat renal inner medulla are modulated by vasopressin V1 and/or V2 antagonists." American Journal of Physiology-Renal Physiology 267, no. 1 (July 1, 1994): F146—F152. http://dx.doi.org/10.1152/ajprenal.1994.267.1.f146.
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For the purpose of clarifying the role of vasopressin V1 and V2 receptors in osmolyte accumulation, we determined the effects on the inner medullary osmolyte content of the administration of orally active vasopressin V1 and/or V2 receptor antagonists OPC-21268 (i.e., 1-(1-[4-(3-acetylaminopropoxy)benzoyl]-4-piperidyl)- 3,4-dihydro-2(1H)-quinolinone) and OPC-31260 (i.e., 5-dimethylamino-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tet rah ydro-1H- benzazepine] under a condition of maximal urine concentration achieved by water deprivation for 4 days. Taurine content increased significantly with the use of the V2 antagonist, irrespective of the use of the V1 antagonist. Inner medullary betaine content decreased with the administration of the V1 antagonist, irrespective of the administration of V2 antagonist. The administration of either the V1 or V2 antagonist alone did not affect sorbitol content, aldose reductase activity, or aldose reductase mRNA abundance in renal inner medulla. However, the combined administration of the V1 and V2 antagonists decreased all of these significantly. Myo-inositol content was not affected by the administration of the V1 or V2 antagonists. Glycerophosphorylcholine content was decreased with the use of the V2 antagonist, irrespective of the use of the V1 antagonist, and this effect paralleled urine osmolality. In conclusion, the individual organic osmolytes responded differently to the antagonists of vasopressin V1 and/or V2 receptors. The mechanisms linked to vasopressin V1 and/or V2 receptors appeared to modulate the accumulation of some organic osmolytes in the inner medulla. Aldose reductase mRNA abundance and sorbitol accumulation in the inner medulla appeared to be mediated through either V1 or V2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)
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Williams, P. D., and D. J. Pettibone. "Recent Advances in the Development of Oxytocin Receptor Antagonists." Current Pharmaceutical Design 2, no. 1 (February 1996): 41–58. http://dx.doi.org/10.2174/1381612802666220920215228.
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Abstract: During the last decade there has been significant progress in the design and discovery of new structural classes of oxytocin antagonists. Continued study of oxytocin analogs has led to the design of antagonists. The similar topography of important functionalities in peptide and non-peptide oxytocin antagonists suggest the possibility of a common pharmacophore. New modifications to the classical antagonist analogs of oxytocin have provided analogs with significant improvements in potency, dura- tion of action, oxytocin receptor selectivity, and bioavailability by non-parenteral routes of administration. In addition, optimization within two structural classes of non-peptides has provided potent and selective analogs which offer the potential for obtaining a clinically useful, orally bioavailable oxytocin antagonist. Human clinical studies with the peptidic oxytocin antagonist, atosiban, have implicated oxytocin as a potential contributor to the pathophysiology of preterm labor and suggests that oxytocin receptor blockade may offer a useful new method for preventing premature birth.
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Kaler, Gregory, Michael Otto, Alex Okun, and Ilya Okun. "Serotonin Antagonist Profiling on 5HT2A and 5HT2C Receptors by Nonequilibrium Intracellular Calcium Response Using an Automated Flow-Through Fluorescence Analysis System, HT-PS®0." Journal of Biomolecular Screening 7, no. 3 (June 2002): 291–301. http://dx.doi.org/10.1177/108705710200700313.
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Characterization of the potencies of agonists and antagonists in cell-based assays can be complicated by nonequilibrium conditions of functional response. We assessed the potencies of a series of serotonin (5HT) antagonists by inhibition of intracellular calcium response in HEK 293 cells expressing 5HT2A or 5HT2C receptors. An automated system, HT-PS 100, was used to profile the antagonists in two experimental setups: coadministration of agonist and antagonist to cells and preincubation of the cells with antagonist prior to agonist administration. We showed that the antagonist potencies (pIC50 values) determined in the preincubation configuration were close to or exceeded those measured in the coadministration configuration. Closeness of the potencies determined in the two configurations supposedly reflected a rapid antagonist-receptor equilibration, whereas a significantly higher preincubation potency implied slow antagonist dissociation from the receptor. Schild analysis of the inhibition of serotonin-induced cell response by a competitive 5HT2A antagonist, spiperone, showed a typical competitive inhibition pattern when both the agonist and antagonist were applied simultaneously. Contrary to this, an insurmountable diminishing of the maximal cell response to serotonin was observed when the cells were preincubated with spiperone. We conclude that a combination of the coadministration and preincubation experimental setups is necessary for appropriate mechanistic interpretation and quantitative assessment of the antagonist activity when using transient functional readouts.
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Jesen, Ralph J. "Mechanism and site of action of a dopamine D1 antagonist in the rabbit retina." Visual Neuroscience 3, no. 6 (December 1989): 573–85. http://dx.doi.org/10.1017/s0952523800009901.
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AbstractDopamine D1 antagonists have been shown to alter drastically the spontaneous and light-evoked activity of ganglion cells in the rabbit retina (Jensen & Daw, 1984, 1986). A major target of dopaminergic neurons in mammalian retinas appears to be rod All amacrine cells (Pourcho, 1982; Voigt & Wässle, 1987). In the present study, the following questions were addressed: (1) Do dopamine D1 antagonists alter the activity of ganglion cells through actions primarily on rod All amacrine cells? (2) Are the effects of dopamine D1 antagonists on ganglion cells due to an inhibition of dopamine-stimulated adenylate cyclase activity?Using an isolated, superfused retinal preparation, the ability of several pharmacological agents to counteract the physiological effects of the dopamine D1 antagonist (+)-SCH 23390 on rabbit ganglion cells was examined. The glycine antagonist strychnine abolished the effects of (+)-SCH 23390 on the spontaneous and light-evoked activity of OFF-center ganglion cells, whereas the excitatory amino-acid antagonist kynurenic acid abolished the effects of (+)-SCH 23390 on the spontaneous and light-evoked activity of ON-center ganglion cells. The findings obtained with these antagonists can be explained in terms of the known synaptic connections of All amacrine cells.Both 8-(4-chlorophenylthio) cyclic AMP, a membrane-permeable cAMP analog, and forskolin, an activator of adenylate cyclase, reversed the effects of (+)-SCH 23390 on the spontaneous and light-evoked activity of OFF-center ganglion cells but not ON-center ganglion cells. These findings suggest that the effects of dopamine D1 antagonists on OFF-center ganglion cells are due to an inhibition of dopamine-stimulated adenylate cyclase, with the ensuing lowering of cellular cAMP levels. The effects of dopamine D1 antagonists on ON-center ganglion cells appear, however, to be independent of intracellular cAMP levels.
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Schneyer, C. A., M. G. Humphreys-Beher, D. Jirakulsomchok, and H. D. Hall. "Effects of autonomic antagonists and growth factors on activity-mediated hyperplasia of rat parotid." American Journal of Physiology-Gastrointestinal and Liver Physiology 264, no. 4 (April 1, 1993): G763—G766. http://dx.doi.org/10.1152/ajpgi.1993.264.4.g763.
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Administration of the autonomic antagonists atropine (1 mg/kg body wt), propranolol (2 mg/kg body wt), and phenoxybenzamine (2 mg/kg body wt) before the dietary change from all liquid to solid chow prevented an increase in uptake of [3H]thymidine into DNA of rat parotid gland associated with this dietary change. Administration of either the cholinergic antagonist alone or the adrenergic antagonists alone produced partial inhibition. The effects of complete autonomic blockade were not reversed when nerve growth factor (NGF) or epidermal growth factor (EGF) was given immediately after administration of antagonists. The effects of complete autonomic blockade were similar to those seen with surgical removal of the autonomic nerves to the parotid. The increased levels of beta 1-4-galactosyltransferase seen with the dietary change were not evident in rats given both muscarinic and adrenergic antagonists before the change to solid food nor did NGF or EGF reverse these inhibitory effects. Histological observation showed that the surgically denervated gland was morphologically less homogenous than the gland of rats given the antagonists and had infiltrating connective tissue. Nonetheless, with the reduced acinar cell pool, the [3H]thymidine uptake of the denervated parotid and that of antagonist-injected animals was similar.
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Hoekstra, William J., and Brenda L. Poulter. "Combinatorial Chemistry Techniques Applied to Nonpeptide lntegrin Antagonists." Current Medicinal Chemistry 5, no. 3 (June 1998): 195–204. http://dx.doi.org/10.2174/0929867305666220314204036.
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The integrins are cell surface receptors that recognize extracellular matrix adhesive proteins such as fibrinogen, fibronectin, vitronectin, and VCAM-1 (vascular cell adhesion molecule-1). Nonpeptide integrin antagonists designed after the adhesion recognition sequence RGD (Arg-Giy-Asp) not only have displayed efficacy as antithrombotic agents, but also have promise for the treatment of cancer and osteoporosis. Combinatorial organic syntheses of chemical mini-libraries have facilitated nonpeptide lead optimization of integrin antagonists with marked success. Although these accomplishments have been realized primarily for the discovery of orally active GPIIb/llla antagonist antithrombotics, vitronectin receptor (αvβ3) antagonist research has also benefited from such rapid synthesis. The purpose of this review is to report progress in combinatorial synthesis lead optimization by highlighting the drug design strategies and synthetic tactics that have led to improved integrin antagonists.
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Sung, Ki-Wug, Sukwoo Choi, and David M. Lovinger. "Activation of Group I mGluRs Is Necessary for Induction of Long-Term Depression at Striatal Synapses." Journal of Neurophysiology 86, no. 5 (November 1, 2001): 2405–12. http://dx.doi.org/10.1152/jn.2001.86.5.2405.
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Activation of metabotropic glutamate receptors (mGluRs), which are coupled to G proteins, has important roles in certain forms of synaptic plasticity including corticostriatal long-term depression (LTD). In the present study, extracellular field potential and whole cell voltage-clamp recording techniques were used to investigate the effect of mGluR antagonists with different subtype specificity on high-frequency stimulation (HFS)-induced LTD of synaptic transmission in the striatum of brain slices obtained from 15-to 25-day-old rats. Induction of LTD was prevented during exposure to the nonselective mGluR antagonist (RS)-α-methyl-4-carboxyphenylglycine (500 μM). The group I mGluR-selective antagonists ( S)-4-carboxy-phenylglycine (50 μM) and (RS)-1-aminoindan-1,5-dicarboxylic acid (100 μM) prevented induction of LTD when applied before and during HFS. The mGluR1-selective antagonist 7-(Hydroxyimino) cyclopropa[b]chromen-1a-carboxylate ethyl ester (80 μM) also blocked LTD induction. Unexpectedly, the mGluR5-selective antagonist 2-methyl-6-(phenylethyl)-pyridine (10 μM) also prevented LTD induction. The group II mGluR antagonist LY307452 (10 μM) did not block LTD induction at corticostriatal synapses, but LY307452 was able to block transient synaptic depression induced by the group II agonist LY314593. None of the antagonists had any effect on basal synaptic transmission at the concentrations used, and mGluR antagonists did not reverse LTD when applied beginning 20 min after HFS. These results suggest that both group I mGluR subtypes contribute to the induction of LTD at corticostriatal synapses.
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Feng, Hong-Qiang, Nate D. Weymouth, and Don C. Rockey. "Endothelin antagonism in portal hypertensive mice: implications for endothelin receptor-specific signaling in liver disease." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 1 (July 2009): G27—G33. http://dx.doi.org/10.1152/ajpgi.90405.2008.
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Endothelin-1 (ET-1), a potent vasoactive peptide, plays an important role in the pathogenesis of liver disease and portal hypertension. Two major endothelin receptors (ET-A and ET-B) mediate biological effects, largely on the basis of their known downstream signaling pathways. We hypothesized that the different receptors are likely to mediate divergent effects in portal hypertensive mice. Liver fibrosis and cirrhosis and portal hypertension were induced in 8-wk-old male BALB/c mice by gavage with carbon tetrachloride (CCl4). Portal pressure was recorded acutely during intravenous infusion of endothelin receptor antagonists in normal or portal hypertensive mice. In vivo microscopy was used to monitor sinusoidal dynamics. Additionally, the effect of chronic exposure to endothelin antagonists was assessed in mice during induction of fibrosis and cirrhosis with CCl4 for 8 wk. Intravenous infusion of ET-A receptor antagonists into normal and cirrhotic mice reduced portal pressure whereas ET-B receptor antagonism increased portal pressure. A mixed endothelin receptor antagonist also significantly reduced portal pressure. Additionally, the ET-A receptor antagonist caused sinusoidal dilation, whereas the ET-B receptor antagonist caused sinusoidal constriction. Chronic administration of each the endothelin receptor antagonists during the induction of fibrosis and portal hypertension led to reduced fibrosis, a significant reduction in portal pressure, and altered sinusoidal dynamics relative to controls. Acute effects of endothelin receptor antagonists are likely directly on the hepatic and sinusoidal vasculature, whereas chronic endothelin receptor antagonism appears to be more complicated, likely affecting fibrogenesis and the hepatic microcirculation. The data imply a relationship between hepatic fibrogenesis or fibrosis and vasomotor responses.
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Burka, John F., Heather Briand, Peter Scott-Savage, and Franco M. Pasutto. "Leukotriene D4 and platelet-activating factor – acether antagonists on allergic and arachidonic acid-induced reactions in guinea pig airways." Canadian Journal of Physiology and Pharmacology 67, no. 5 (May 1, 1989): 483–90. http://dx.doi.org/10.1139/y89-077.
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Arachidonic acid (AA) and ovalbumin (OA) were used to induce contractions of sensitized guinea pig tracheal spiral (indomethacin-pretreated) and lung parenchymal strip preparations. This model was used to examine the properties of three leukotriene (LT) D4 antagonists and a platelet-activating factor (PAF)–acether receptor antagonist. The three LTD4 antagonists, L-649,923, FPL 57231, and LY163443, inhibited AA-induced contractions of indomethacin-pretreated tracheal spirals selectively. The PAF–acether antagonist, L-652,731, did not inhibit AA-induced contractions of either trachea or parenchyma. This confirmed that AA-induced contractions of trachea involved release and activity of LTD4. The LTD4 antagonists and L-652,731 partially inhibited OA-induced contractions of both trachea and parenchyma. When L-649,923 and L-652,731 or FPL 57231 and L-652,731 were combined, an additive inhibitory effect on OA-induced contractions was observed. When LY163443 and L-652,731 were combined, the inhibitory effect was synergistic. This may be due to the additional effect of LY163443 to inhibit phosphodiesterase. Total inhibition of OA-induced contractions was obtainable with relatively low concentrations when a LTD4 and PAF–acether antagonist were combined. These results suggested that LTD4 and PAF–acether may be the two major mediators in our model of allergic bronchospasm. The LTD4 and PAF–acether antagonists had the capacity to decrease baseline tone, even on tissues that were already relaxed with indomethacin, suggesting that LTD4 and PAF–acether may contribute to intrinsic tone in airway smooth muscle.Key words: leukotriene D4, platelet-activating factor, airway smooth muscle, antagonists, allergic bronchospasm.
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Castaldo, C., T. Benicchi, M. Otrocka, E. Mori, E. Pilli, P. Ferruzzi, S. Valensin, et al. "CXCR4 Antagonists." Journal of Biomolecular Screening 19, no. 6 (March 14, 2014): 859–69. http://dx.doi.org/10.1177/1087057114526283.
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The CXC chemokine receptor 4 (CXCR4) is a widely expressed G protein–coupled receptor implicated in several diseases. In cancer, an increased number of surface CXCR4 receptors, in parallel with aberrant signaling, have been reported to influence several aspects of malignancy progression. CXCR4 activation by the specific ligand C-X-C motif chemokine 12 (CXCL12) induces several intracellular signaling pathways that have been selectively related to malignancy depending on the tissue or cell type. We developed a panel of CXCR4 screening assays investigating Gαi-mediated cyclic adenosine monophosphate modulation, β-arrestin recruitment, and receptor internalization. All of the assays were set up in recombinant cells and were used to test four reported CXCR4 antagonists. Consequently, a set of hit compounds, deriving from a screening campaign of a 30,000-small-molecule internal library, was profiled with the different assays. We identified several compounds showing a pathway-selective activity: antagonists on a Gαi-dependent pathway; antagonists on both the β-arrestin and Gαi-dependent pathways, some of which induce receptor internalization; and compounds with an antagonist behavior in all of the readouts. The identified biased antagonists induce different functional states on CXCR4 and preferentially affect specific downstream responses from the activated receptor, thus providing an improved therapeutic profile for correction of CXCR4 abnormal signaling.
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Schisler, D. A., N. I. Khan, M. J. Boehm, and P. J. Slininger. "Greenhouse and Field Evaluation of Biological Control of Fusarium Head Blight on Durum Wheat." Plant Disease 86, no. 12 (December 2002): 1350–56. http://dx.doi.org/10.1094/pdis.2002.86.12.1350.
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Fusarium head blight (FHB) is a devastating disease that causes extensive yield and quality losses to wheat and barley. In durum wheat, the pathogen-produced toxin deoxynivalenol (DON) is retained in semolina at ˜50%, and the causal agent of FHB, Gibberella zeae, has a strong adverse effect on pasta color. Two bacteria and two yeast strains with known efficacy against G. zeae on hexaploid wheats were produced in liquid culture and assayed on two cultivars of durum wheat in greenhouse bioassays. All antagonists reduced FHB severity on cultivar Renville, and three of the four reduced severity on cultivar Ben, with Bacillus subtilis strain AS 43.3 decreasing FHB severity by as much as 90%. In separate greenhouse bioassays, the car-bon:nitrogen ratio of the medium used to produce antagonists did not consistently influence antagonist efficacy. All antagonist/production medium combinations but one were effective in reducing disease on both durum cultivars. Of six antagonists tested at field sites, Cryptococcus sp. OH 71.4 and C. nodaensis OH 182.9 reduced disease severity by as much as 57% in Peoria, IL, while Cryptococcus sp. OH 181.1 reduced disease severity by as much as 59% in a trial at Langdon, ND. Antagonists did not influence the DON content of grain in the Peoria trial. Relative performance indices for four antagonists calculated from greenhouse and field results on the two durum cultivars demonstrated that the bioassay location, but not the cultivar of durum, influenced the relative performance of antagonists. Yeast antagonists OH 71.4, OH 181.1, and OH 182.9 appear to have the highest potential for contributing to the reduction of FHB on du-rum wheat in the field.
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Helm II, Standiford. "Opioid Antagonists, Partial Agonists, and Agonists/Antagonists: The Role of OfficeBased Detoxification." Pain Physician 2;11, no. 3;2 (March 14, 2008): 225–35. http://dx.doi.org/10.36076/ppj.2008/11/225.
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Background: The opioid receptor antagonists naloxone and naltrexone are competitive antagonists at the mu, kappa, and sigma receptors with a higher affinity for the mu receptor and lacking any mu receptor efficacy. Buprenorphine is classified as a partial agonist. It has a high affinity, but low efficacy at the mu receptor where it yields a partial effect upon binding. It also, however, possesses kappa receptor antagonist activity making it useful not only as an analgesic, but also in opioid abuse deterrence, detoxification, and maintenance therapies. Naloxone is added to sublingual buprenorphine (Suboxone®) to prevent the intravenous abuse of buprenorphine. The same product (sublingual buprenorphine) when used alone (i.e. without naloxone) is marketed as Subutex®. Objective: To evaluate and update the available evidence regarding the use of agonist/antagonists to provide office-based opioid treatment for addiction. Methods: A review using databases of EMBASE and MEDLINE (1992 to December 2007). These included systematic reviews, narrative reviews, prospective and retrospective studies, as well as cross-references from other articles. Outcome Measures: The primary outcome measure was treatment retention. Other outcome measures included opioid-free urine drug testing, opioid craving, intensity of withdrawal, pain reduction, adverse effects, addiction severity index, and HIV risk behavior. Results: The results found 17 studies, 1 systematic review, 12 RCTs, and 4 observational series, which document the efficacy and safety of buprenorphine alone and in combination with naloxone in detoxifying and maintaining abstinence from illicit drugs in patients with opioid addiction. Conclusion: Based on the present evaluation, it appears that opioid antagonists, partial agonists, and antagonists are useful in office-based opioid treatment for addiction. Key words: Opioid, antagonist, partial agonist, tolerance, dependence, detoxification, withdrawal, hyperalgesia, buprenorphine, naloxone, naltrexone, methylnaltrexone, butorphanol, nalbuphine, pentazocine
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Wang, Zhicheng, Suping Li, Guanglei Liu, Quanwei Shi, Rong Yan, Changgeng Ruan, and Kesheng Dai. "Inhibition of Calmodulin Triggers Apoptosis Events in Human Platelets." Blood 114, no. 22 (November 20, 2009): 3003. http://dx.doi.org/10.1182/blood.v114.22.3003.3003.
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Abstract Abstract 3003 Poster Board II-980 Calmodulin (CaM) is a calcium-sensing protein ubiquitously expressed in every eukaryotic cell type regulating biological processes such as cell proliferation, vesicular fusion, fertilization and apoptosis. CaM antagonists induce apoptosis in various tumor models and inhibit tumor cell invasion and metastasis, thus some of which have been extensively used as anti-cancer agents. Tamoxifen (TMX), a potent antagonist of CaM, has been in the center of management of hormone-sensitive breast cancer, and also represents the best example of chemo-prevention to reduce the incidence of invasive breast cancer. Furthermore, TMX is potentially useful in treatment of other kinds of cancer. However, TMX has some severe side effects, one of which is thrombocytopenia. Up to now, the pathogenesis of thrombocytopenia still remains unclear. In platelets, CaM has been found to bind directly to cytoplasmic domains of several platelet receptors. Incubation of platelets with CaM antagonists impairs the receptors-related platelet function. However, it is still unclear whether CaM antagonists, especially TMX, induce platelet apoptosis. Here, we show that CaM antagonists TMX and N-(6-aminohexyl)-5-chloro-1-naphthalene sulfonamide (W7) dose-dependently induce apoptotic events in human platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 activation, gelsolin cleavage and phosphatidylserine (PS) exposure. CaM antagonist did not incur platelet activation as detected by P-selectin surface expression and PAC-1 binding. However, ADP- and botrocetin-induced platelet aggregation and platelet adhesion and spreading on von Willebrand factor surface were significantly reduced in platelets pre-treated with CaM antagonist. Therefore, these findings indicate that CaM antagonists induce platelet apoptosis, which suggests a possible pathogenesis of thrombocytopenia in some patients treated with CaM antagonist drugs, and also may present as a novel mechanism for platelet clearance and dysfunction in vivo or in vitro. The elevation of the cytosolic Ca2+ level may involve in the regulation of CaM antagonist-induced platelet apoptosis. Disclosures: No relevant conflicts of interest to declare.
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Benveniste, M., J. M. Mienville, E. Sernagor, and M. L. Mayer. "Concentration-jump experiments with NMDA antagonists in mouse cultured hippocampal neurons." Journal of Neurophysiology 63, no. 6 (June 1, 1990): 1373–84. http://dx.doi.org/10.1152/jn.1990.63.6.1373.
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1. Voltage-clamp experiments were used to study N-methyl-D-aspartic acid (NMDA) receptor antagonists applied by fast perfusion to mouse hippocampal neurons in dissociated culture. 2. Preincubation with the NMDA antagonists zinc (3-30 microM) and magnesium (30-300 microM) reduced subsequent responses to 100 microM NMDA applied together with these antagonists. No time dependence of antagonism was observed when responses were measured at the start and at the end of NMDA pulses 1.25-1.5 s in duration. 3. Two competitive antagonists of similar affinity in equilibrium experiments, D-2-amino-5-phosphonopentanoic acid (D-AP5) and 3-((+-)-2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), had different profiles of action when applied as described above. With D-AP5, pulses of NMDA produced fast-on, fast-off responses, of reduced amplitude, similar to the effect of Zn and Mg. Responses to NMDA in the presence of CPP were also of reduced amplitude but, in addition, showed slow activation, such that the antagonist action of CPP decreased with time after the application of NMDA. 4. In the presence of 3 microM glycine and NMDA receptor antagonists with activity at the glycine modulatory site, either kynurenic acid (Kyn), 7-chlorokynurenic acid (7Cl-Kyn), or 5-chloro-indole-2-carboxylic acid (5Cl-I2CA), NMDA-evoked responses showed apparent use-dependent antagonism, such that the peak response to NMDA was much greater than the equilibrium response. A similar effect was produced by preincubation with low concentrations of glycine (less than 300 nM), which enhances desensitization of responses to NMDA. The apparent use-dependent action of glycine antagonists could be reversed on raising the glycine concentration and did not vary appreciably with changes in membrane potential over the range -60 to +50 mV. 5. Concentration-jump application of NMDA antagonists, in the presence of 100 microM NMDA and 3 microM glycine, were used to study antagonist association and dissociation kinetics directly. For D-AP5 and CPP, the dissociation rate was independent of antagonist concentration, and approximately 15 times faster for D-AP5 (19.6 s-1) than for CPP (1.36 s-1). The association rate for D-AP5 and CPP increased with antagonist concentration in a linear manner over the range 3-30 microM and was slower for CPP than for D-AP5, consistent with their similar potency at equilibrium. 6. In contrast to results obtained with CPP and D-AP5, the association rate for 7Cl-Kyn was approximately 3 times slower than the dissociation rate and did not change with concentration of antagonist.(ABSTRACT TRUNCATED AT 400 WORDS)
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Watanabe, Katsushige, and Minoru Kimura. "Dopamine Receptor–Mediated Mechanisms Involved in the Expression of Learned Activity of Primate Striatal Neurons." Journal of Neurophysiology 79, no. 5 (May 1, 1998): 2568–80. http://dx.doi.org/10.1152/jn.1998.79.5.2568.
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Watanabe, Katsushige and Minoru Kimura. Dopamine receptor–mediated mechanisms involved in the expression of learned activity of primate striatal neurons. J. Neurophysiol. 79: 2568–2580, 1998. To understand the mechanisms by which basal ganglia neurons express acquired activities during and after behavioral learning, selective dopamine (DA) receptor antagonists were applied while recording the activity of striatal neurons in monkeys performing behavioral tasks. In experiment 1, a monkey was trained to associate a click sound with a drop of reward water. DA receptor antagonists were administered by micropressure using a stainless steel injection cannula (300 μm ID) through which a Teflon-coated tungsten wire for recording neuronal activity had been threaded. Responses to sound by tonically active neurons (TANs), a class of neurons in the primate striatum, were recorded through a tungsten wire electrode during the application of either D1- or D2-class DA receptor antagonists (total volume <1 μl, at a rate of 1 μl/5–10 min). Application of the D2-class antagonist, (−)-sulpiride (20 μg/μl, 58 mM, pH 6.8), abolished the responses of four of five TANs examined. In another five TANs, neither the D2-class antagonist nor the D1-class antagonists, SCH23390 (10 μg/μl, 31 mM, pH 5.7) or cis-flupenthixol (30 μg/μl, 59 mM, pH 6.6) significantly suppressed responses. In experiment 2, four- or five-barreled glass microelectrodes were inserted into the striatum. The central barrel was used for extracellular recording of activity of TANs. Each DA receptor antagonist was iontophoretically applied through one of the surrounding barrels. SCH23390 (10 mM, pH 4.5) and (−)-sulpiride (10 mM, pH 4.5) were used. The effects of iontophoresis of both D1- and D2-class antagonists were examined in 40 TANs. Of 40 TANs from which recordings were made, responses were suppressed exclusively by the D2-class antagonist in 19 TANs, exclusively by the D1-class antagonist in 3 TANs, and by both D1- and D2-class antagonists in 7 TANs. When 0.9% NaCl, saline, was applied by pressure (<1 μl) or by iontophoresis (<30 nA) as a control, neither the background discharge rates nor the responses of TANs were significantly influenced. Background discharge rate of TANs was also not affected by D1- or D2-class antagonists applied by either micropressure injection or iontophoresis. It was concluded that the nigrostriatal DA system enables TANs to express learned activity primarily through D2-class and partly through D1-class receptor–mediated mechanisms in the striatum.
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Root, Thomas S., and David J. Quan. "Histamine2-Receptor Antagonists Do Not Prevent Allergic Reactions." Journal of Pharmacy Technology 10, no. 2 (March 1994): 58–60. http://dx.doi.org/10.1177/875512259401000204.
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Objective: To determine whether histamine2 (H2)-receptor antagonists are effective in the treatment of allergic reactions such as rhinitis and urticaria. Methods: A MEDLINE search of current literature revealed 13 journal articles for review. Literature evaluation was conducted. Conclusions: H2-antagonists alone did not seem to prevent allergic reactions. While further studies are needed to clearly define the mechanism of the beneficial effects seen with combined H1.- and H2-antagonist therapy, there are no convincing data to suggest that H2-antagonists used alone have any therapeutic value in the prevention of allergic rhinitis or urticaria.
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Andriastini, Dewa Ayu, Yan Ramona, and Meitini Wahyuni Proborini. "In Vitro Inhibition of Fungal Antagonists on Fusarium sp., the Disease Causative Agent on Dragon Fruit Plant (Hylocereus undatus (Haw.) Britton & Rose)." Metamorfosa: Journal of Biological Sciences 5, no. 2 (October 18, 2018): 224. http://dx.doi.org/10.24843/metamorfosa.2018.v05.i02.p14.
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A research on in vitro inhibition of fungal antagonists, isolated from dragon fruit plantation in Sembung village, Bali, on Fusarium sp. (the disease causative agent of dragon fruit plant) was conducted with the main objective to investigate the effectiveness of these fungal antagonists to inhibit the in vitro growth of the pathogen. Dual assay method was applied in this experiment. The results showed that three potential fungal antagonists were successfully isolated in this research and they were identified as Trichoderma harzianum, Aspergillus niger, dan Paecilomyces lilacinus. All these fungal antagonists showed antagonistic activity against Fusarium sp. which was statistically significant (p<0.05) when compared to control. This indicated that all antagonist isolates were potential to be developed as biocontrol agent candidates.
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Hin, Sascha, Claus Zabel, Alberto Bianco, Günther Jung, and Peter Walden. "Cutting Edge: N-Hydroxy Peptides: A New Class of TCR Antagonists." Journal of Immunology 163, no. 5 (September 1, 1999): 2363–67. http://dx.doi.org/10.4049/jimmunol.163.5.2363.
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Abstract TCR antagonists are altered T cell epitopes that specifically inactivate T cells. Commonly, they are derived from agonists by amino acid side chain replacement at positions accessible to the TCR. In this paper we report for the first time that a main chain N-hydroxylation, which is not exposed at the surface of the MHC peptide complex, renders an agonist into an antagonist. These mimotopes are a new, yet undescribed class of TCR antagonists. The antagonists are about 100 times more potent than an unrelated peptide that competes for binding to the MHC molecule. The novel main chain modification enhances biostability and maintains side chain constitution and thus opens new prospects for the use of TCR antagonists in the treatment of pathological immune reactions.
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Skolnick, Phil, Tomasz Kos, Janusz Czekaj, and Piotr Popik. "Effect of NMDAR antagonists in the tetrabenazine test for antidepressants: comparison with the tail suspension test." Acta Neuropsychiatrica 27, no. 4 (April 10, 2015): 228–34. http://dx.doi.org/10.1017/neu.2015.14.
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ObjectiveThe N-methyl-d-aspartate receptor (NMDAR) antagonist ketamine, produces rapid and enduring antidepressant effect in patients with treatment-resistant depression. Similar dramatic effects have not been observed in clinical trials with other NMDAR antagonists indicating ketamine may possess unique pharmacological properties. Tetrabenazine induces ptosis (a drooping of the eyelids), and the reversal of this effect, attributed to a sympathomimetic action, has been used to detect first-generation antidepressants, as well as ketamine. Because the actions of other NMDAR antagonists have not been reported in this measure, we examined whether reversal of tetrabenazine-induced ptosis was unique to ketamine, or a class effect of NMDAR antagonists.MethodsThe effects of ketamine and other NMDAR antagonists to reverse tetrabenazine-induced ptosis were examined and compared with their antidepressant-like effects in the tail suspension test (TST) in mice.ResultsAll the NMDAR antagonists tested produced a partial reversal of tetrabenazine-induced ptosis and, as expected, reduced immobility in the TST. Ketamine, memantine, MK-801 and AZD6765 were all about half as potent in reversing tetrabenazine-induced ptosis compared to reducing immobility in the TST, while an NR2B antagonist (Ro 25-6981) and a glycine partial agonist (ACPC) were equipotent in both tests.ConclusionThe ability to reverse tetrabenazine-induced ptosis is a class effect of NMDAR antagonists. These findings are consistent with the hypothesis that the inability of memantine, AZD6765 (lanicemine) and MK-0657 to reproduce the rapid and robust antidepressant effects of ketamine in the clinic result from insufficient dosing rather than a difference in mechanism of action among these NMDAR antagonists.
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Abdel-Basset, R. "Calcium/Calmodulin Regulated Cell Wall Regeneration in Zea mays Mesophyll Protoplasts." Zeitschrift für Naturforschung C 53, no. 1-2 (February 1, 1998): 33–38. http://dx.doi.org/10.1515/znc-1998-1-208.
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Abstract The composition of newly synthesized cell walls starting from enzymatically isolated Zea mays mesophyll protoplasts was studied. The contents of pectin, cellulose and hemicellulose in addition to the wall-associated proteins were followed in the presence of increasing concentrations of calcium ions with or without the calcium channel blockers like lanthanum, lithium ions, verapamil, nifedipine and the calmodulin antagonist trifluperazine. Pectin accumulation was inhibited by all antagonists except lanthanum. Cellulose formation, however, was increased by organic antagonists trifluperazine, verapamil and maximally by nifedipine while it was not affected by the inorganic ions lanthanum or lithium. Hemicellulose accumu lated with nifedipine present but significantly decreased by all other antagonists. Added Ca2+ (5 -10 mᴍ) reversed most of the blockers-induced inhibition on pectin and hemicellulose. In the case of cellulose, however, calcium concentration which reversed the inhibitory action of these antagonists was dependent on the antagonist. Starch exhibited little alterations indicat ing its minor role in deposition of wall components. Cell wall-associated proteins were negatively affected by lanthanum and verapamil and positively by lithium and nifedipine. Generally, this fraction was found in a negative correlation with pectin levels. Chlorophyll contents were lowered after growth for 48 h; this might be due to repeated cell division. These results are discussed in relation to the mechanism of antagonists and effects of calcium.
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Fernandes, Maria F., Michelle V. Tomczewski, and Robin E. Duncan. "Glucagon-like Peptide-1 Secretion Is Inhibited by Lysophosphatidic Acid." International Journal of Molecular Sciences 23, no. 8 (April 9, 2022): 4163. http://dx.doi.org/10.3390/ijms23084163.
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Glucagon-like peptide-1 (GLP-1) potentiates glucose-stimulated insulin secretion (GSIS). While dozens of compounds stimulate GLP-1 secretion, few inhibit. Reduced GLP-1 secretion and impaired GSIS occur in chronic inflammation. Lysophosphatidic acids (LPAs) are bioactive phospholipids elevated in inflammation. The aim of this study was to test whether LPA inhibits GLP-1 secretion in vitro and in vivo. GLUTag L-cells were treated with various LPA species, with or without LPA receptor (LPAR) antagonists, and media GLP-1 levels, cellular cyclic AMP and calcium ion concentrations, and DPP4 activity levels were analyzed. Mice were injected with LPA, with or without LPAR antagonists, and serum GLP-1 and DPP4 activity were measured. GLUTag GLP-1 secretion was decreased ~70–90% by various LPAs. GLUTag expression of Lpar1, 2, and 3 was orders of magnitude higher than Lpar4, 5, and 6, implicating the former group in this effect. In agreement, inhibition of GLP-1 secretion was reversed by the LPAR1/3 antagonist Ki16425, the LPAR1 antagonists AM095 and AM966, or the LPAR2 antagonist LPA2-antagonist 1. We hypothesized involvement of Gαi-mediated LPAR activity, and found that intracellular cyclic AMP and calcium ion concentrations were decreased by LPA, but restored by Ki16425. Mouse LPA injection caused an ~50% fall in circulating GLP-1, although only LPAR1 or LPAR1/3 antagonists, but not LPAR2 antagonism, prevented this. GLUTag L-cell and mouse serum DPP4 activity was unchanged by LPA or LPAR antagonists. LPA therefore impairs GLP-1 secretion in vitro and in vivo through Gαi-coupled LPAR1/3 signaling, providing a new mechanism linking inflammation with impaired GSIS.
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Seto, Jeremy, Liang Qiao, Carolin A. Guenzel, Sa Xiao, Megan L. Shaw, Fernand Hayot, and Stuart C. Sealfon. "Novel Nipah Virus Immune-Antagonism Strategy Revealed by Experimental and Computational Study." Journal of Virology 84, no. 21 (August 25, 2010): 10965–73. http://dx.doi.org/10.1128/jvi.01335-10.
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ABSTRACT Nipah virus is an emerging pathogen that causes severe disease in humans. It expresses several antagonist proteins that subvert the immune response and that may contribute to its pathogenicity. Studies of its biology are difficult due to its high pathogenicity and requirement for biosafety level 4 containment. We integrated experimental and computational methods to elucidate the effects of Nipah virus immune antagonists. Individual Nipah virus immune antagonists (phosphoprotein and V and W proteins) were expressed from recombinant Newcastle disease viruses, and the responses of infected human monocyte-derived dendritic cells were determined. We developed an ordinary differential equation model of the infectious process that that produced results with a high degree of correlation with these experimental results. In order to simulate the effects of wild-type virus, the model was extended to incorporate published experimental data on the time trajectories of immune-antagonist production. These data showed that the RNA-editing mechanism utilized by the wild-type Nipah virus to produce immune antagonists leads to a delay in the production of the most effective immune antagonists, V and W. Model simulations indicated that this delay caused a disconnection between attenuation of the antiviral response and suppression of inflammation. While the antiviral cytokines were efficiently suppressed at early time points, some early inflammatory cytokine production occurred, which would be expected to increase vascular permeability and promote virus spread and pathogenesis. These results suggest that Nipah virus has evolved a unique immune-antagonist strategy that benefits from controlled expression of multiple antagonist proteins with various potencies.
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Hogendorf, Agata, Adam S. Hogendorf, Rafał Kurczab, Grzegorz Satała, Bernadeta Szewczyk, Paulina Cieślik, Gniewomir Latacz, et al. "N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential." Molecules 26, no. 15 (July 29, 2021): 4605. http://dx.doi.org/10.3390/molecules26154605.
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A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.
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Kishimoto, T., J. M. Chawla, K. Hagi, C. A. Zarate, J. M. Kane, M. Bauer, and C. U. Correll. "Single-dose infusion ketamine and non-ketamine N-methyl-d-aspartate receptor antagonists for unipolar and bipolar depression: a meta-analysis of efficacy, safety and time trajectories." Psychological Medicine 46, no. 7 (February 12, 2016): 1459–72. http://dx.doi.org/10.1017/s0033291716000064.
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BackgroundKetamine and non-ketamine N-methyl-d-aspartate receptor antagonists (NMDAR antagonists) recently demonstrated antidepressant efficacy for the treatment of refractory depression, but effect sizes, trajectories and possible class effects are unclear.MethodWe searched PubMed/PsycINFO/Web of Science/clinicaltrials.gov until 25 August 2015. Parallel-group or cross-over randomized controlled trials (RCTs) comparing single intravenous infusion of ketamine or a non-ketamine NMDAR antagonist v. placebo/pseudo-placebo in patients with major depressive disorder (MDD) and/or bipolar depression (BD) were included in the analyses. Hedges’ g and risk ratios and their 95% confidence intervals (CIs) were calculated using a random-effects model. The primary outcome was depressive symptom change. Secondary outcomes included response, remission, all-cause discontinuation and adverse effects.ResultsA total of 14 RCTs (nine ketamine studies: n = 234; five non-ketamine NMDAR antagonist studies: n = 354; MDD = 554, BD = 34), lasting 10.0 ± 8.8 days, were meta-analysed. Ketamine reduced depression significantly more than placebo/pseudo-placebo beginning at 40 min, peaking at day 1 (Hedges' g = −1.00, 95% CI −1.28 to −0.73, p < 0.001), and loosing superiority by days 10–12. Non-ketamine NMDAR antagonists were superior to placebo only on days 5–8 (Hedges' g = −0.37, 95% CI −0.66 to −0.09, p = 0.01). Compared with placebo/pseudo-placebo, ketamine led to significantly greater response (40 min to day 7) and remission (80 min to days 3–5). Non-ketamine NMDAR antagonists achieved greater response at day 2 and days 3–5. All-cause discontinuation was similar between ketamine (p = 0.34) or non-ketamine NMDAR antagonists (p = 0.94) and placebo. Although some adverse effects were more common with ketamine/NMDAR antagonists than placebo, these were transient and clinically insignificant.ConclusionsA single infusion of ketamine, but less so of non-ketamine NMDAR antagonists, has ultra-rapid efficacy for MDD and BD, lasting for up to 1 week. Development of easy-to-administer, repeatedly given NMDAR antagonists without risk of brain toxicity is of critical importance.
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Scarborough, Robert M. "Structure-Activity Relationships of Amino Acid-Containing lntegrin Antagonists." Current Medicinal Chemistry 6, no. 10 (October 1999): 971–81. http://dx.doi.org/10.2174/092986730610220401161259.
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Interest in the development of specific antagonists of the 3 family of integrins {platelet aub3 and the vitronectin receptor av3 ) has been principally driven by efforts to design more potent antithrombotic agents than either aspirin or the thienopyridine-type ADP receptor modulators. The platelet fibrinogen receptor (aub3) and the vitronectin receptor (av 3) bind the RGD tripeptide sequence found within adhesive ligands. Because of this, many approaches to antagonists of 3 receptors have utilized an RGD mimetic to identify antagonists. lntegrin antagonists of many structurally diverse classes have been discovered. One of the larger 3 integrin antagonist classes employs -amino acids to mimic the aspartate residue of the RGD mimetic. Structure-activity investigations have revealed the potent activity of agents which have substituents appended to both the a and position of the -amino acid units of these antagonists. Several clinical candidates targeting platelet a11 b3 contain these -amino acid units and are currently being evaluated clinically.
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Shang, Liangcheng, Yaobiao Huang, Xin Xie, Sudan Ye, and Chun Chen. "Effect of Adenosine Receptor Antagonists on Adenosine-Pretreated PC12 Cells Exposed to Paraquat." Dose-Response 20, no. 2 (April 2022): 155932582210934. http://dx.doi.org/10.1177/15593258221093411.
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Previous studies evaluated the adenosine receptor antagonists alone to determine their effects on oxidative stress, but little is known about adenosine’s protective efficacy when oxidative injury occurs in vivo. Adenosine is a crucial signaling molecule recognized by four distinct G-protein-coupled receptors (GPCRs) (i.e., A1R, A2AR, A2BR, and A3R) and protects cells against pathological conditions. The present study was performed to evaluate the role of antagonist modulation in the setting of paraquat toxicity with adenosine pretreatment. First, PC12 cells were exposed to paraquat (850 μM) and adenosine (30 μM) to develop an in vitro model for the antagonist effect assay. Second, we found that the A1R antagonist DPCPX enhanced the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Moreover, the A2AR antagonist ZM241385 decreased the viability of paraquat-induced PC12 cells that underwent adenosine pretreatment. Our findings indicate that adenosine protection requires a dual blockade of A1R and activation of A2AR to work at its full potential, and the A2B and A3 adenosine receptor antagonists increased paraquat-induced oxidative damage. This represents a novel pharmacological strategy based on A1/A2A interactions and can assist in clarifying the role played by AR antagonists in the treatment of neurodegenerative diseases.
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Lehmberg, Jens, Jürgen Beck, Alexander Baethmann, and Eberhard Uhl. "Bradykinin Antagonists Reduce Leukocyte–Endothelium Interactions after Global Cerebral Ischemia." Journal of Cerebral Blood Flow & Metabolism 23, no. 4 (April 2003): 441–48. http://dx.doi.org/10.1097/01.wcb.0000052280.23292.35.
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The aim of the present study was to evaluate the influence of bradykinin on microcirculatory changes and outcome after global cerebral ischemia (15 minute) in Mongolian gerbils. The cerebral microcirculation was investigated by fluorescent intravital microscopy. Survival and functional outcome was evaluated up to 4 d after ischemia. Animals were treated with the selective B1 and B2 receptor antagonists B 9858 and CP 0597, respectively, and the nonselective B1/B2 receptor antagonist B 9430. Leukocyte activation was significantly reduced by all antagonists as indicated by a significant decrease in the number of rolling (33 ± 20, 6 ± 8, 9 ± 10, and 13 ± 10) and adherent leukocytes (9 ± 7, 3 ± 4, 1 ± 1, and 2 ± 3 · 100 μm–1 · min–1 in controls and in animals treated with B1, B2, and B1/B2 antagonist, respectively). Arteriolar diameters were significantly reduced during reperfusion (35 ± 11 before and 27 ± 8 μm 40 minutes after ischemia) in animals treated with the B2 antagonist. The postischemic hypoperfusion, however, was not affected. Mortality was significantly higher in animals treated with the B1 and the B1/B2 antagonist. The authors concluded that bradykinin is involved in postischemic disturbances of cerebral microcirculation. The therapeutic effect of specific bradykinin receptor antagonists on functional outcome, however, remains unclear.