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J J Foley

Publications and source records attributed to J J Foley.

At least 55 records · Page 3Linked to original sources
PubMed1993

Synthesis of structural analogs of leukotriene B4 and their receptor binding activity.

Structural analogs of leukotriene B4 (LTB4) were designed using a preferred conformation of LTB4 (1). Appending an aromatic ring scaffold between LTB4 carbons 7 and 11 led to quinoline analogs 3 and 15. A similar modification to the LTB4 structure between carbons 7 and 9 led to the pyridine analogs 41 and 46. The compounds of this study were evaluated in receptor binding assays using [3H]LTB4 and intact human DMSO differentiated U-937 cells. The first analog prepared, quinoline 3, displayed moderate potency in the LTB4 receptor binding assay (Ki = 0.9 microM). Modification of 3 by appending an aromatic ring between carbons 2 and 4 of the acid side chain produced a dramatic increase in receptor binding (15, Ki = 0.01 microM); a further improvement in receptor binding was achieved in the pyridine series (e.g., 41; Ki = 0.001 microM). The LTB4 receptor agonist/antagonist activity of the test compounds was determined using a functional assay that relies upon intracellular calcium mobilization induced by LTB4. Of the analogs prepared in this report only 47 demonstrated LTB4 receptor antagonist activity.

Humans↗
PubMed1993

Trisubstituted pyridine leukotriene B4 receptor antagonists: synthesis and structure-activity relationships.

A series of trisubstituted pyridines have been prepared that exhibit in vitro leukotriene B4 (LTB4, 1) receptor antagonist activity. Previous disubstituted pyridines from these labs showed high affinity for the LTB4 receptor but demonstrated agonist activity in functional assays (e.g., 2, Ki = 1 nM). Compound 4, the initial lead compound of this new series, showed only modest affinity by comparison (Ki = 282 nM); however, 4 was a receptor antagonist with no demonstrable agonist activity up to 10 microM. Subsequent modifications of the lipid tail and aryl head group region led to the discovery of aniline 50 (SB 201146). This compound, also free of agonist activity, possesses high affinity for the LTB4 receptor (Ki = 4.7 nM).

Acrylates↗
PubMed1993

Synthesis and LTB4 receptor antagonist activities of the naturally occurring LTB4 receptor antagonist Leucettamine A and related analogues.

The isolation and structure determination of the naturally occurring LTB4 receptor antagonist Leucettamine A (1) was recently reported. Herein we describe the synthesis of this natural product, the preparation of several analogues, and their effectiveness as antagonists of [3H]LTB4 binding to intact human U-937 cells. Total synthesis of Leucettamine A (1) is achieved by a convergent route which takes advantage of the elements of symmetry within the molecule. Syntheses of analogues of 1, which lacked the same degree of symmetry, are achieved by a different approach starting from alpha-amino acids. The natural product 1 inhibits [3H]LTB4 binding to its receptors on intact human U-937 cells with a Ki = 3.5 +/- 0.8 microM and is devoid of measurable agonist activity at the concentrations tested. 2-Amino imidazole analogues of 1 lacking the dioxolane groups were prepared. Generally these are significantly less potent than 1. However, one (26), designed on the basis of a putative structural overlay with LTB4, demonstrated potency comparable to that of the natural product (Ki = 2.4 +/- 0.2 microM).

Calcium↗
PubMed1993

Association between leukotriene B4-induced phospholipase D activation and degranulation of human neutrophils.

We have explored the role of phospholipase D (PLD) activation in leukotriene B4 (LTB4)-induced Ca2+ mobilization and degranulation of human neutrophils. Stimulation of [3H]alkyl-acyl-phosphatidylcholine-labeled neutrophils with LTB4 resulted in a rapid accumulation of [3H]alkyl-phosphatidic acid (PA) as well as a somewhat slower accumulation of [3H]alkyl-diglyceride (DG). In the presence of ethanol, PLD catalyzed a transphosphatidylation reaction in which LTB4 increased [3H]alkyl-phosphatidylethanol formation and simultaneously decreased LTB4-induced PA and DG accumulation. This pattern of lipid metabolism is consistent with the conclusion that LTB4 stimulates PLD activity in human neutrophils. Additional studies in which the extracellular and intracellular concentrations of Ca2+ were varied indicated that maximal LTB4-induced PLD activation was dependent upon Ca2+ and potentiated by inhibitors of protein kinase C. The time-course and concentration-response curves for LTB4-induced PLD activation were different from those for LTB4-induced Ca2+ mobilization, as measured by fura-2 fluorescence. On the other hand, the concentration-response curve for LTB4-induced PLD activation was similar to that for LTB4-induced degranulation. Preincubation of the cells with ethanol inhibited LTB4-induced PA and DG accumulation, as well as degranulation, suggesting that one or both of these metabolites were important for this response. In contrast, ethanol had no effect on LTB4-induced Ca2+ mobilization. Propranolol, an inhibitor of phosphatidate phosphohydrolase, abolished DG accumulation in response to LTB4 but had no effect on degranulation, suggesting that PA is more important than DG as a mediator of degranulation. Taken collectively, these data indicate that LTB4-induced activation of PLD in human neutrophils is mediated by a Ca(2+)-dependent mechanism, but not by protein kinase C. In addition, PLD activation in these cells may induce degranulation, but not Ca2+ mobilization.

Alkaloids↗
PubMed1993

Considerations in the use of benzodiazepines and antipsychotics in the emergency department.

Agitated patients may come to the emergency department because of flares of a psychiatric illness, drug withdrawal, or reaction to a medical condition or trauma. Pharmacologic agents such as lorazepam may offer benefits to these patients, regardless of the cause of their symptoms. It is important to be familiar with the dosage, administration, and onset of effects of the commonly used agents. The emergency nurse should be aware that akathisia in a patient receiving an antipsychotic medication is not agitation and should not be treated with a higher dose of an antipsychotic drug. The nurse needs to be able to recognize other adverse effects (e.g., acute dystonic reactions), reassure the patient, and administer the treatment to relieve the adverse effect. If the patient's chart from a previous ED visit is readily available, it is a good idea to identify the drug treatment that was successful in the past. The same drug at the same dosage is likely to be effective again. For patients discharged home, it is important to ensure that these patients will be able to obtain the necessary maintenance medication and that they have a follow-up visit planned before they leave the emergency department.

Antipsychotic Agents↗
PubMed1993

Recognition and treatment of neuroleptic malignant syndrome.

NMS remains a serious and unpredictable reaction to central nervous system dopamine blockade. Use of the more recent, flexible definition of NMS will ensure that patients with this syndrome receive prompt effective diagnosis and treatment. Supportive care, discontinuation of the neuroleptic drug, and administration of bromocriptine are the keys to appropriate management. For patients with hypertension, nifedipine may be a useful alternative or adjunctive treatment. Because these patients may not be able to communicate, the role of the emergency nurse includes not only administration of supportive and pharmacologic care but also reassurance that this frightening disorder is treatable, with improvement likely within 1 day.

Combined Modality Therapy↗
PubMed1993

Pharmacologic treatment of acute migraine and related headaches in the emergency department.

The care that an emergency nurse delivers is critical to the success of treatment of acute headaches. The emergency nurse should obtain a medication history from the patient and offer reassuring information about the relief afforded by prescribed medications and the adverse effects that can occur. Because the best treatment for a patient with recurrent headache syndrome is prevention, the emergency nurse should make sure that appropriate follow-up (e.g., headache specialist or counselor) is arranged before discharge from the emergency department.

Acute Disease↗
PubMed1992

Stimulation of leukotriene production and membrane translocation of 5-lipoxygenase by cross-linking of the IgE receptors in RBL-2H3 cells.

Recent studies in rat basophilic leukemia cells (RBL-2H3) have shown that two pharmacological agents, ionomycin and thapsigargin, induce leukotriene C4 production and translocation of 5-lipoxygenase from cytosol to membrane, primarily by causing an influx of extracellular calcium. In the present study, we investigate the induction of these events by receptor activation. Cross-linking of high-affinity IgE receptors (Fc epsilon RI) by antigen in RBL-2H3 cells leads to leukotriene C4 production and membrane translocation of 5-lipoxygenase. As in the ionomycin-stimulated cells, leukotriene C4 production in antigen-stimulated cells is calcium-dependent since the amount of leukotriene C4 produced correlates quantitatively with the increase in intracellular free calcium concentration ([Ca2+]i). However, the increase in [Ca2+]i required for equivalent leukotriene C4 production by antigen is not as high as it is using ionomycin. In addition, no threshold [Ca2+]i level is required for leukotriene production by antigen, which is in contrast to the ionomycin stimulation that a [Ca2+]i level of 300-400 nM is required. Furthermore, antigen causes an additive increase in leukotriene C4 production in cells stimulated by the ionomycin. These results suggest that another as yet unidentified intracellular pathway acts in conjunction with Ca2+ for leukotriene synthesis in antigen-stimulated cells. Antigen stimulation causes 20-30% of the total cell 5-lipoxygenase to associate with membranes (compared with 10% in unstimulated cells) as demonstrated by enzyme activity assay and by Western Blot using antibodies to 5-lipoxygenase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Influx of extracellular calcium is required for the membrane translocation of 5-lipoxygenase and leukotriene synthesis.

Our studies assessed the effects of increases in intracellular calcium concentrations [( Ca2+]i) on leukotriene synthesis and membrane translocation of 5-lipoxygenase (5LO). The calcium ionophore ionomycin and the tumor promoter thapsigargin stimulated leukotriene production and translocation of 5-lipoxygenase to the membrane. Both agents elicited prolonged rises in [Ca2+]i. Leukotriene C4 production associated with [Ca2+]i in cells stimulated with various concentrations of ionomycin and thapsigargin suggests that a threshold [Ca2+]i level of approximately 300-400 nM is required. In the absence of extracellular Ca2+, both the ionomycin- and thapsigargin-induced rises in [Ca2+]i were transient, indicating that the prolonged [Ca2+]i elevation is due to an influx of extracellular Ca2+. Addition of EGTA to the external medium before, or at different times during, the treatment with ionomycin or thapsigargin instantaneously inhibited 5LO translocation and leukotriene synthesis, indicating that Ca2+ influx plays an essential role in 5LO membrane translocation and leukotriene synthesis. No leukotriene production was detected when cells were stimulated by a physiological stimulus of leukotriene D4. The addition of 100 nM leukotriene D4 triggered peak rises in [Ca2+]i that were comparable to those achieved by the ionomycin and thapsigargin. However, the leukotriene D4 induced rise was transient and rapidly declined to a lower but still elevated steady-state level, which was attributed to Ca2+ influx. Stimulation with 100 nM leukotriene D4 for 15 s increased the cellular levels of 1,4,5-inositol triphosphate (IP3), 1,3,4-IP3, and 1,3,4,5-inositol tetraphosphate (IP4).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Transient activation of topoisomerase I in leukotriene D4 signal transduction in human cells.

U937 human monoblast cells incubated with leukotriene D4 (LTD4) rapidly released arachidonic acid metabolites into the culture medium. Release was suppressed by the high-affinity LTD4 receptor antagonist SK&F 104353. Arachidonic acid release induced by LTD4 has been linked to a rapid induction of gene expression, and the propagation of the receptor binding signal is probably associated with enzymes that regulate gene expression. We have studied the participation of DNA topoisomerase I in LTD4 signal transduction. LTD4-specific release of arachidonic acid metabolites was inhibited (60-80%) by the topoisomerase I inhibitor camptothecin. LTD4 increased protein-linked DNA strand breakage induced by camptothecin in U937 cells; this enhancement was prevented by coincubation of the cells with LTD4 plus the receptor antagonist SK&F 104353. In addition, LTD4 produced a rapid transient increase in extractable topoisomerase I activity, which was maximum within the first 10 min after addition of LTD4 to the culture medium. Incubation of cultures for greater than 10 min with LTD4 before the addition of camptothecin resulted in no enhancement of camptothecin-induced DNA strand breakage, consistent with a reversal of topoisomerase I activation. Staurosporine, an inhibitor of protein kinase C, blocked LTD4-induced arachidonic acid release and attenuated the effect of LTD4 on camptothecin-induced DNA strand breakage. These results are consistent with the view that the regulation of topoisomerase I activity is involved in the propagation of LTD4-mediated signals in U937 cells.

Alkaloids↗
PubMed1990

15-Acetylthioxy-furodysinin lactone, isolated from a marine sponge Dysidea, sp. is a potent agonist to human leukotriene B4 receptor.

A sesquiterpene thioacetate, 15-acetylthioxy-furodysinin (SK&F 105900) has been isolated from the sponge Dysidea SP. This compound can bind specifically to the human peripheral blood polymorphonuclear leukocyte (PMN) and to the differentiated human monocytic leukemic U-937 cell membrane leukotriene B4 (LTB4) receptors with high-affinity. This compound can also promote a concentration-dependent chemotaxis in PMNs and an intracellular calcium mobilization in U-937 cells that can be blocked by the LTB4 receptor antagonist, LY-223982. Furthermore, the calcium mobilization induced by SK&F 105900 can specifically cross-desensitize with the LTB4-induced calcium mobilization. These observations indicate that SK&F 105900 is a novel and specific high-affinity agonist that can bind to the LTB4 receptors and activate the receptor-mediated signal transduction processes in human PMN and U-937 cells.

Animals↗
PubMed1990

Inhibitors of protein kinase C selectively enhanced leukotriene D4-induced calcium mobilization in differentiated U-937 cells.

U-937 cells differentiated with dimethylsulphoxide for 3-4 days express receptors for leukotriene D4 (LTD4), which are coupled to Ca2+ mobilization and phosphatidylinositol (PI) metabolism. Treatment of U-937 cells with an inhibitor of protein kinase C (PKC) [staurosporine (100 nM)] augmented the Ca2+ mobilized by LTD4. The peak concentration of the LTD4-induced increase in [Ca2+]i was 1500 nM in untreated cells and 3000 nM in cells treated with staurosporine for 30 s. Maximal mobilization responses were observed at 1-10 microM LTD4 in both control and staurosporine-treated cells. The increased Ca2+ response to LTD4 after staurosporine treatment occurred within 30 s and was attributable to both intracellular and extracellular stores. Additionally, a second phase of Ca2+ mobilization occurred after stimulation with LTD4, which was elevated by pretreatment with staurosporine--this effect was maximal after 5-10 min of treatment. Staurosporine either had no effect or decreased the Ca2+ mobilization response of differentiated U-937 cells to other agonists, such as LTB4, platelet activating factor, ATP or the chemotactic peptide f-Met-Leu-Phe. Although staurosporine alone had no effect on basal PI metabolism it increased LTD4-induced PI metabolism. Staurosporine did not prevent the tachyphylaxis observed upon second challenge with LTD4, nor did it prevent LTD4-induced homologous densensitization. Other compounds which inhibit PKC (sphingosine and 1-O-hexadecyl-2-O-methylglycerol), also enhanced the Ca2+ response of U-937 cells to LTD4, but not to other agonists. These data show that inhibition of PKC enhanced responses of LTD4, suggesting that PKC plays a role in determining the responsiveness of LTD4 receptors.

Alkaloids↗
PubMed1989

Mechanisms of leukotriene E4 partial agonist activity at leukotriene D4 receptors in differentiated U-937 cells.

Leukotriene E4 (LTE4) is shown to be a partial agonist of leukotriene D4 (LTD4) in differentiated U-937 cells. The data that support this conclusion are: 1) LTE4 completely displaced [3H]LTD4 from its receptors in U-937 cell membranes. 2) LTE4 induced only 30 +/- 4% of the maximal Ca2+ transient induced by LTD4 in the presence of 1 mM extracellular Ca2+ and 60 +/- 4% of the maximal LTD4 response in the absence of extracellular Ca2+. 3) LTE4 induced only a fraction of the inositol phosphates metabolized by LTD4. Moreover, LTE4 resulted in essentially no production of the inositol 1,4,5-trisphosphate isomer, while LTD4 induced a rapid and substantial transient increase in this isomer. The generation of inositol phosphates by both agonists was unaffected by extracellular Ca2+. 4) The EC50 values for Ca2+ mobilization for LTD4 and LTE4 corresponded with their affinity (Kd values) for the LTD4 receptor. 5) A series of structurally diverse LTD4 receptor antagonists blocked the Ca2+ mobilization responses to LTD4 and LTE4 with identical rank orders of potency. 6) LTE4 acted as an antagonist of LTD4 of potency. 6) LTE4 acted as an antagonist of LTD4 effects when they were coadministered. 7) LTE4 and LTD4 acutely desensitized Ca2+ mobilization to each other. All of the effects of LTE4 are explained by its partial agonist activity at the LTD4 receptor as shown by the following data. 1) Neither LTD4 nor LTE4 had any effect on the agonist activity of fMet-Leu-Phe, LTB4, or platelet-activating factor. 2) None of the above agonists or antagonists to the above receptors affected any of the activities of LTD4 or LTE4. 3) Neither LTD4 nor LTE4 induced desensitization of Ca2+ mobilization to any of the non-LTD4 receptor agonists tested. 4) Under the conditions studied, we have not observed any evidence of multiple subclasses of LTD4 receptors in U-937 cells. LTE4 is a partial agonist of the LTD4 receptor, because it can only couple the LTD4 receptor to a portion of the signaling system available to the receptor when occupied by LTD4. Specifically, LTD4 caused the activation of receptor-operated calcium channels, mobilization of intracellular Ca2+, the activation of phosphatidylinositol-phospholipase C, and the liberation of an additional, as yet undefined, intracellular mediator. To do this, LTD4 receptors couple to at least two and perhaps more guanine nucleotide binding proteins. LTE4 is unable to activate the phosphatidylinositol-phospholipase C but can mimic the other effects of LTD4.(ABSTRACT TRUNCATED AT 400 WORDS)

Benzofurans↗
PubMed1988

Phorbol 12-myristate 13-acetate inhibition of leukotriene D4-induced signal transduction was rapidly reversed by staurosporine.

Activation of leukotriene D4 receptors results in phospholipase C-mediated breakdown of phosphatidylinositol and increases in intracellular Ca2+ in U-937 cells. Treatment (10 min) with phorbol 12-myristate 13-acetate blocked leukotriene D4-induced phosphatidylinositol metabolism and Ca2+ mobilization (IC50 = 0.2 nM). Treatment with 10 nM phorbol 12-myristate 13-acetate produced blockade which was complete within 1 min and no recovery was observed over 7 days. Addition of the protein kinase C inhibitor staurosporine (100 nM) to U-937 cells pretreated with phorbol 12-myristate 13-acetate for 5 min or 24 hr resulted in a rapid reappearance of leukotriene D4-induced Ca2+ mobilization. Half of the response recovered within 2 min, with complete recovery in 20 min. Staurosporine produced a concentration-related recovery of signal transduction, with an EC50 of 30 nM. These data describe cells which have a novel response to phorbol 12-myristate 13-acetate in that the inhibition of leukotriene D4 signal transduction is persistent and yet rapidly reversed by staurosporine.

Alkaloids↗