ChemInform Abstract: 3-Substituted-4-hydroxy-7-chromanylacetic Acid Derivatives as Antagonists of the Leukotriene B4 (LTB4) Receptor.

ChemInform ◽  
2010 ◽  
Vol 28 (52) ◽  
pp. no-no
Author(s):  
L. A. REITER ◽  
ET AL. ET AL.
Keyword(s):  
Leukotriene B4 ◽  
Ltb4 Receptor

The design and synthesis of second generation leukotriene B4 (LTB4) receptor antagonists related to SC-41930

1993 ◽  
Vol 39 (S1) ◽  
pp. C11-C13 ◽  
Author(s):  
T. D. Penning ◽  
S. W. Djuric ◽  
S. H. Docter ◽  
S. S. Yu ◽  
D. Spangler ◽  
...  
Keyword(s):  
Second Generation ◽  
Leukotriene B4 ◽  
Receptor Antagonists ◽  
Design And Synthesis ◽  
Ltb4 Receptor

scholarly journals Inhibition of leukotriene B4-receptor interaction suppresses eosinophil infiltration and disease pathology in a murine model of experimental allergic encephalomyelitis.

1996 ◽  
Vol 183 (4) ◽  
pp. 1893-1898 ◽  
Author(s):  
R P Gladue ◽  
L A Carroll ◽  
A J Milici ◽  
D N Scampoli ◽  
H A Stukenbrok ◽  
...  
Keyword(s):  
Experimental Allergic Encephalomyelitis ◽  
Murine Model ◽  
Light And Electron Microscopy ◽  
Leukotriene B4 ◽  
Eosinophil Infiltration ◽  
Receptor Interaction ◽  
Allergic Encephalomyelitis ◽  
Leukotriene B4 Receptor ◽  
Experimental Allergic ◽  
Ltb4 Receptor

Leukotriene B4 (LTB4) is a chemotactic and cell-activating factor present at inflammatory sites in a variety of autoimmune diseases including multiple sclerosis (MS). In this study, we used a murine model of MS, experimental allergic encephalomyelitis (EAE), to assess the potential role of LTB4 on cell infiltration and paralysis. Injection of encephalogenic T cells into naive animals induced paralysis and weight loss that was completely inhibited by treatment with the selective LTB4 receptor antagonist CP-105,696 (ED50= 8.6 mg/kg orally). Although migration of lymphocytes into the central nervous system was unaffected, the efficacious effects of CP-105,696 correlated with up to a 97% decrease in eosinophil infiltration into the lower spinal cord as determined by light and electron microscopy and quantitated by levels of the specific enzyme marker eosinophil peroxidase. These results demonstrate that eosinophil recruitment in EAE is dependent on LTB4 receptor ligation and further reveal a previously unrecognized role for eosinophils in the pathogenesis of this disease.

The LTB4 Receptor Is Involved Not Only in the Downstream Pathway of rh-GCSF Mobilization but in the LTB4 Mobilization Pathway in C57BL/6 Mice.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5216-5216
Author(s):  
Yeung-Chul Mun ◽  
Seung-Eun Lee ◽  
Kyoung-Eun Lee ◽  
Eun-Sun Yoo ◽  
Sang Min Lee ◽  
...  
Keyword(s):  
Leukotriene B4 ◽  
Dependent Manner ◽  
Receptor Antagonists ◽  
Hematopoietic Stem ◽  
Normal Individuals ◽  
Blocking Effects ◽  
Blue Stain ◽  
Cell Mobilization ◽  
Dose Levels ◽  
Ltb4 Receptor

Abstract Though we were able to shorten the CD34+ cell mobilization by 24~48h by using continuous intravenous rhG-CSF rather than SQ rhG-CSF, it still will take several days when used normal individuals (Lee et al, BMT2005, 36:1027–1031). Previously we had reported that LT(Leukotriene)B4 was able to mobilize HSC in the murine model within 4 hours without significant side effects(ASH 2005). However, because there are possibilities of similar mechanisms during the HSC mobilization, which are shared by rhG-CSF or LTB4, in this study, we investigated the role of LTB4 receptors by rhG-CSF during HSC mobilization. LTB4APA and U75302, which are LTB4 receptor antagonists were given to C57BL/6 mice at different dose levels(0.5μg, 1μg, 2μg or PBS with equal volume in control arm) followed by rhG-CSF(5μg, IV) 2 hours later. 24 hours after the rhG-CSF injection, peripheral blood samples were obtained via cardiac puncture. The samples were analyzed for TNC using a trypan blue stain and FACS analysis were performed using Sca-1, Lin, CD45R(B220), CD116, Gr-1, TER119. The number of WBC and HSC were decreased in the rhG-CSF mobilized mice, in which LTB4 receptor antagonists were given. In those with up to 1μg of LTB4APA or U75302, there were tendencies of the blocking of the mobilization in the dose dependent manner. However, beyond 1μg of LTB4 receptor antagonists, the blocking effects plateaued. Interestingly, the blocking effects on mobilization by LTB4 receptor antagonists were more dramatic by the rh-GCSF than by the LTB4. Through our data, one can conclude that the LTB4 receptor is involved not only in the downstream pathway of rh-GCSF mobilization, but in the LTB4 mobilization pathway in C57BL/6 mice. Currently, hematopoietic stem cells mobilization is being tested to see the effects of rh-GCSF on LTB4 K/O mice. It is necessary to have insight into understandings more precise mechanisms on rhG-CSF and LTB4 mobilization for developing efficient protocols in the clinic.

trans-3-Benzyl-4-hydroxy-7-chromanylbenzoic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor

1998 ◽  
Vol 8 (14) ◽  
pp. 1781-1786 ◽  
Author(s):  
Lawrence A. Reiter ◽  
Kevin Koch ◽  
Anthony D. Piscopio ◽  
Henry J. Showell ◽  
Robbin Alpert ◽  
...  
Keyword(s):  
Leukotriene B4 ◽  
Ltb4 Receptor

scholarly journals Transition of affinity states for leukotriene B4 receptors in sheep lung membranes

1990 ◽  
Vol 265 (3) ◽  
pp. 841-847 ◽  
Author(s):  
B Votta ◽  
S Mong
Keyword(s):  
G Protein ◽  
Rank Order ◽  
Alkali Treatment ◽  
Leukotriene B4 ◽  
Guanine Nucleotide ◽  
Single Class ◽  
Receptor Affinity ◽  
Arachidonate Metabolite ◽  
Guanine Nucleotide Binding ◽  
Ltb4 Receptor

Leukotriene B4 (LTB4) is a pro-inflammatory arachidonate metabolite. We have characterized the LTB4 receptors in sheep lung membranes and have assessed the contribution of the guanine-nucleotide-binding (G) protein in the regulation of receptor affinity states. Saturation isotherms have demonstrated a single class of LTB4 receptor with a Kd of 0.18 +/- 0.03 nM and a density (Bmax.) of 410 +/- 84 fmol/mg of protein in sheep lung membranes. The effect of the G-protein on receptor affinity was assessed in the presence of non-hydrolysable GTP analogues (e.g. GTP[S]) and in membranes following alkali treatment (pH 12.1) to remove the G-protein. Saturation isotherms produced either in the presence of GTP[S] (Kd.GTP[S] = 0.51 +/- 0.02 nM) or with alkali-treated membranes (Kd.alk. = 0.52 +/- 0.02 nM) demonstrated a 3-fold shift in receptor affinity for [3H]LTB4 binding. In competition experiments, the rank order of affinity of LTB4 analogues was LTB4 greater than 20-OH-LTB4 greater than trans-homo-LTB4 greater than 6-trans-LTB4 greater than 20-COOH-LTB4, using either untreated or alkali-treated membranes, both in the presence and absence of GTP[S]. These findings demonstrate that, in sheep lung membranes, there is only one class of LTB4 receptor. Removal of the G-protein or uncoupling of the receptor from the G-protein shifted the agonist-binding affinity of the receptor by 3-4-fold, without affecting the specificity of the LTB4 receptor in either the high- or the low-affinity state.

scholarly journals Leukotriene B4 stimulation of phagocytes results in the formation of inositol 1,4,5-trisphosphate A second messenger for Ca2+ mobilization

1986 ◽  
Vol 240 (2) ◽  
pp. 333-340 ◽  
Author(s):  
T Andersson ◽  
W Schlegel ◽  
A Monod ◽  
K H Krause ◽  
O Stendahl ◽  
...  
Keyword(s):  
Regulatory Protein ◽  
Receptor Activation ◽  
Leukotriene B4 ◽  
Human Neutrophils ◽  
Leukaemia Cell Line ◽  
Hl60 Cells ◽  
Transduction Mechanism ◽  
Inositol 1,4,5 Trisphosphate ◽  
Bordetella Pertussis Toxin ◽  
Ltb4 Receptor

Inositol trisphosphate (InsP3) production and cytosolic free Ca2+ ([Ca2+]i) elevations induced by leukotriene B4 (LTB4)-receptor activation were studied in the human promyelocytic-leukaemia cell line HL60, induced to differentiate by retinoic acid. The myeloid-differentiated HL60 cells respond to LTB4 by raising their [Ca2+]i with a dose-response relationship similar to that shown by normal human neutrophils. The observations of the LTB4 transduction mechanism were compared with those of the transduction mechanism of the chemotactic peptide fMet-Leu-Phe in HL60 cells differentiated with dimethyl sulphoxide. Both LTB4 and fMet-Leu-Phe triggered a rapid (less than 5 s) elevation of [Ca2+]i, which occurred in parallel with the InsP3 production from myo-[3H]inositol-labelled cells. The threshold concentrations of the agonists, for InsP3 production, were found at 10(-9) M, a slightly higher concentration than that required to detect [Ca2+]i elevations. No significant changes were noted in the phosphoinositide levels upon stimulation with LTB4. Exposure to Bordetella pertussis toxin before LTB4 stimulation abolished both the increased formation of InsP3 and the rise of [Ca2+]i. LTB4 and fMet-Leu-Phe elicited elevations of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] with no detectable lag time, followed by slower and more sustained inositol 1,3,4-trisphosphate elevations. Stimulation with various leukotriene analogues revealed a good correlation between both total InsP3 as well as Ins(1,4,5)P3 formation and elevations of [Ca2+]1. Thus LTB4 receptor activation results in an increased production of Ins(1,4,5)P3 via a transduction mechanism also involving a nucleotide regulatory protein, as previously described for the fMet-Leu-Phe transduction mechanism.

Leukotriene B4 costimulates 5-lipoxygenase activity in neutrophils via increased 5-lipoxygenase translocation

1997 ◽  
Vol 272 (4) ◽  
pp. C1329-C1334 ◽  
Author(s):  
K. J. Serio ◽  
J. R. Baker ◽  
W. L. Ring ◽  
C. A. Riddick ◽  
T. D. Bigby
Keyword(s):  
Arachidonic Acid ◽  
Biological Significance ◽  
Leukotriene B4 ◽  
Lipoxygenase Activity ◽  
Nuclear Fraction ◽  
Arachidonic Acid Release ◽  
Product Release ◽  
A 23187 ◽  
Acid Release ◽  
Ltb4 Receptor

The goal of this investigation was to assess the effect of leukotriene B4 (LTB4) on 5-lipoxygenase activity and to examine the possible mechanisms of this effect. Exogenous LTB4 significantly increased the release of endogenous LTB4 from A-23187-stimulated neutrophils. The 5-lipoxygenase product release from A-23187-stimulated neutrophils decreased in the presence of an LTB4 receptor antagonist, suggesting that LTB4 has a receptor-mediated, autocrine effect on 5-lipoxygenase activity. Neutrophil 5-lipoxygenase activity increased significantly as cell density increased. In the presence of exogenous LTB4, no significant change in [14C]arachidonic acid release from neutrophils was observed. Exogenous LTB4 increased the amount of immunoreactive 5-lipoxygenase protein detected in the nuclear fraction of disrupted cells. LTB4 receptor antagonism decreased the amount of immunoreactive 5-lipoxygenase detected in the nuclear fraction. Thus LTB4 exerts an autocrine, receptor-mediated, costimulatory effect on 5-lipoxygenase activity. This feedback appears to have biological significance and involves enhanced 5-lipoxygenase translocation to the nuclear membrane.

New serine protease inhibitors with leukotriene B4 (LTB4) receptor binding affinity

1997 ◽  
Vol 5 (5) ◽  
pp. 971-985 ◽  
Author(s):  
Yoshisuke Nakayama ◽  
Kazuhiko Senokuchi ◽  
Katsuhito Sakaki ◽  
Masashi Kato ◽  
Toru Maruyama ◽  
...  
Keyword(s):  
Serine Protease ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Receptor Binding ◽  
Leukotriene B4 ◽  
Serine Protease Inhibitors ◽  
Receptor Binding Affinity ◽  
Ltb4 Receptor

scholarly journals Bltr Mediates Leukotriene B4–Induced Chemotaxis and Adhesion and Plays a Dominant Role in Eosinophil Accumulation in a Murine Model of Peritonitis

2000 ◽  
Vol 192 (3) ◽  
pp. 439-446 ◽  
Author(s):  
Andrew M. Tager ◽  
Jennifer H. Dufour ◽  
Katayoon Goodarzi ◽  
Scott D. Bercury ◽  
Ulrich H. von Andrian ◽  
...  
Keyword(s):  
Dominant Role ◽  
Leukotriene B4 ◽  
Calcium Flux ◽  
Leukocyte Activation ◽  
Functional Roles ◽  
Leukocyte Function ◽  
Inflammatory Processes ◽  
Ltb4 Receptor

Leukotriene B4 (LTB4) is a potent chemoattractant active on multiple leukocytes, including neutrophils, macrophages, and eosinophils, and is implicated in the pathogenesis of a variety of inflammatory processes. A seven transmembrane–spanning, G protein–coupled receptor, called BLTR (LTB4 receptor), has recently been identified as an LTB4 receptor. To determine if BLTR is the sole receptor mediating LTB4-induced leukocyte activation and to determine the role of LTB4 and BLTR in regulating leukocyte function in inflammation in vivo, we generated a BLTR-deficient mouse by targeted gene disruption. This mouse reveals that BLTR alone is responsible for LTB4-mediated leukocyte calcium flux, chemotaxis, and firm adhesion to endothelium in vivo. Furthermore, despite the apparent functional redundancy with other chemoattractant–receptor pairs in vitro, LTB4 and BLTR play an important role in the recruitment and/or retention of leukocytes, particularly eosinophils, to the inflamed peritoneum in vivo. These studies demonstrate that BLTR is the key receptor that mediates LTB4-induced leukocyte activation and establishes a model to decipher the functional roles of BLTR and LTB4 in vivo.

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