Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.4.1 (phosphodiesterase)
18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Several new drugs are now under development for the treatment of asthma, either as improvements to existing classes of therapy or as novel agents. Amongst bronchodilators, long-acting inhaled beta 2-agonists (salmeterol and formoterol) look very promising and there is also interest in selective phosphodiesterase inhibitors, K+ channel-openers and nitrodilators. There are several new inhaled corticosteroids under development and more selective agents include leukotriene antagonists, 5-lipoxygenase inhibitors, bradykinin and tachykinin antagonists and immunomodulators. In the future, adhesion molecule inhibitors and cytokine inhibitors may be developed.
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PMID:New drugs for asthma. 135 72

1. Responses of antigen-challenged isolated trachea from sensitized guinea-pigs were pharmacologically characterized by use of some novel inhibitors and antagonists of arachidonic acid metabolites. 2. The cyclo-oxygenase inhibitor, indomethacin, prolonged without altering the maximum response to antigen in the absence of the anti-muscarinic agent, atropine, and/or the H1-receptor blocker, mepyramine. In the presence of mepyramine, indomethacin both prolonged and increased the magnitude of the response. The selective (SQ-29548) and non-selective (L-640,035) thromboxane A2 (TXA2) antagonist and the TXA2 synthetase inhibitor, OKY-046, were essentially inactive. 3. Two novel inhibitors of 5-lipoxygenase product formation, AA-861 and L-651,896 produced complete inhibition of the response to antigen on tissues treated with atropine and mepyramine, with or without indomethacin. 4. Equimolar concentrations of the leukotriene D4 (LTD4) receptor antagonists LY-171883 greater than L-649,923 greater than or equal to L-648,051 greater than or equal to FPL-55712 blocked part of the response to antigen on tissues treated with atropine, mepyramine and indomethacin. All compounds tended to block a larger component of the response in the absence of indomethacin. A similar tendency was observed with the potent phosphodiesterase inhibitor, isobutylmethylxanthine (IBMX) but not the less potent phosphodiesterase inhibitor theophylline. 5. These results are consistent with the hypothesis that 5-lipoxygenase products acting on LTD4 receptors play only a minor role in the mediation of the contraction of guinea-pig trachea to antigen challenge. The nature of the residual contractile mediator is unknown; however, it can be completely blocked by the 5-lipoxygenase inhibitors AA-861 and L-651,896 and non-selectively blocked by the phosphodiesterase inhibitor, IBMX and non-selective LTD4 receptor antagonists, such as LY-171883.
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PMID:Antigen-induced contraction of guinea-pig isolated trachea: studies with novel inhibitors and antagonists of arachidonic acid metabolites. 246 87

Zymosan, carrageenan, arachidonic acid and platelet activating factor (PAF) were used to induce inflammation (edema) in the paws of mice. Antiinflammatory drugs (e.g., BW 755C and indomethacin) as well as cyproheptadine (mediator antagonist), theophylline (phosphodiesterase inhibitor) and guanabenz (alpha adrenoceptor agonist) showed the greatest efficacy in the carrageenan and zymosan models. Nonsteroidal antiinflammatory (NSAIDs) agents showed greater activity in the arachidonic acid (AA) paw edema model than the dual 5-lipoxygenase (LO)/cyclooxygenase (CO) inhibitors. The PAF model was insensitive to NSAIDs but showed some activity with drugs possessing inhibitory 5-LO activity (e.g., phenidone, BW 755C) and the mediator antagonist, cyproheptadine. Suramin, a complement inhibitor, as expected, was active only against zymosan-induced edema. In conclusion, the inhibitory activities of dual 5-LO/CO inhibitors and NSAIDs were not different in the zymosan, carrageenan and AA edema models in the mouse; however, some selectivity for 5-LO inhibitors was observed in the PAF model.
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PMID:Effect of selected antiinflammatory agents and other drugs on zymosan, arachidonic acid, PAF and carrageenan induced paw edema in the mouse. 312 May 10

The effect of antiinflammatory drugs, phosphodiesterase inhibitors, leukotriene and mediator antagonists and other drug classes were evaluated in a PAF-induced mortality model in mice. By the oral route of administration (-1 hr), dapsone (ED50 = 25 mg/kg), BW 755C (ED50 = 29 mg/kg), theophylline (ED50 = 30 mg/kg) and LY-171,883 (ED50 = 50 mg/kg) protected against PAF-induced lethality in the mouse. Other drugs that afforded protection when given at various dosing schedules and routes were NDGA (100 mg/kg, -18 hr p.o.), diphenyldisulfide (100 mg/kg, -18 hr p.o.), diphenyldisulfide (200 mg/kg, -18 hr p.o.), dexamethasone (1 mg/kg, -3 hr p.o.), dipyridamole (2 mg/kg, -2 min i.v.) and kadsurenone (10 mg/kg, -2 min i.v.). Nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin were inactive and the combination of AA-861, a putative 5-LO inhibitor, and indomethacin also failed to prevent PAF-induced lethality. Therefore, our pharmacological data do not consistently support the notion that PAF-induced lethality is due unequivocally to leukotrienes derived from 5-lipoxygenase metabolism.
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PMID:Pharmacologic modulation of PAF-induced mortality in mice. 312 May 13

1. The effects of REV 5901 on the platelet activating factor (Paf)-induced (a) bronchoconstriction, (b) contraction of lung parenchymal strips and (c) increased airways responsiveness to histamine, were assessed in the guinea-pig. REV 5901 is a 5-lipoxygenase inhibitor and competitive peptidoleukotriene antagonist which does not inhibit multiple forms of phosphodiesterase. 2. In urethane/pentobarbitone anaesthetized animals, REV 5901 (10 or 30 mg kg-1, i.v.) substantially inhibited the bronchoconstriction, measured as changes in airways resistance (RL) and dynamic lung compliance (Cdyn), induced by leukotriene D4 (2.5 micrograms kg-1, i.v.) but did not attenuate that induced by Paf (50 ng kg-1, i.v.). 3. Paf contracted the lung parenchymal strip in a concentration-dependent manner. REV 5901 (25 microM) neither altered the magnitude of the contractions nor the tissue sensitivity to Paf. The sustained contraction induced by Paf was not affected when REV 5901 was added after the response had reached a plateau. 4. Contractions of parenchymal strips to Paf (50 nM) were prevented by pretreatment with the competitive Paf antagonists, SRI 63441 and WEB 2086. Also WEB 2086, but not SRI 63441, reversed established Paf-induced contractions and relaxed parenchymal strips from intrinsic tone in the absence of Paf. 5. Paf (20 ng kg-1, i.v.) caused an acute increase in airways responsiveness to histamine (4-12 micrograms kg-1, i.v.) which was attenuated by REV 5901 at 10 mg kg-1, i.v. and abolished by 30 mg kg-1, i.v. 6. These data suggest that leukotrienes do not participate in Paf-induced bronchoconstriction or contraction of the lung parenchymal strip, but may play a role in the increased responsiveness of the airways to histamine observed after Paf challenge in the guinea-pig.
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PMID:Effects of REV 5901, a 5-lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea-pig. 314 88

Acetyl glyceryl ether phosphorylcholine induces human neutrophil aggregation. Incubation of neutrophils with either prostaglandin I2, or the cyclic AMP-dependent phosphodiesterase inhibitor, RO 20-1724 before the addition of PAF-acether attenuates subsequent aggregation. Paradoxically, a small elevation in cyclic AMP is observed coincident with the initiation of PAF-acether-stimulated aggregation. The elevation in cyclic AMP in response to PAF-acether is amplified by RO 20-1724, and the magnitude of the response is dependent upon the concentration of PAF-acether. The elevation in cyclic AMP is not due to prostaglandins, because indomethacin actually enhances the elevation in cyclic AMP induced by PAF-acether. The involvement of the neutrophil 5-lipoxygenase, and subsequent leukotriene B4 synthesis, is suggested by the observation that 5-lipoxygenase inhibitors limit both the elevation in cyclic AMP induced by PAF-acether, and the indomethacin enhancement. This indirect evidence is supported by the fact that leukotriene B4 itself elevates neutrophil cyclic AMP levels in intact cells, and stimulates the adenylate cyclase in broken cell preparations. Although the elevation in cyclic AMP induced by either PAF-acether or leukotriene B4 is coincident with the onset of neutrophil aggregation, it is not obligatory for aggregation. The adenylate cyclase inhibitor 2',5'-dideoxyadenosine blocks the PAF-acether-stimulated increase in cyclic AMP, and actually enhances aggregation. It is suggested that the increase in cyclic AMP observed after the addition of PAF-acether is due to concomitant leukotriene B4 synthesis, and is not obligatory for neutrophil aggregation, but is actually part of a feed-back regulatory system through which PAF-acether and leukotriene B4 can limit their own activity in neutrophils.
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PMID:Evidence for mediation of acetyl glyceryl ether phosphorylcholine stimulation of adenosine 3',5'-(cyclic)monophosphate levels in human polymorphonuclear leukocytes by leukotriene B4. 631 71

It seems paradoxical that AGEPC induces a transient rise in cyclic AMP, yet the preincubation of neutrophils with agents that elevate cyclic AMP actually inhibits AGEPC-induced aggregation. However, similar transient elevations in cyclic AMP are observed using other stimulators of PMN function such as fmet-leu-phe, C5a (22), immune complexes (24), and phagocytosable particles (11). Elevations in cyclic AMP by PGE1, PGI2, dibutyryl cyclic AMP, and phosphodiesterase inhibitors, before the addition of an agonist, also blocked subsequent neutrophil activation in the above studies. Thus, these observations are not unique to AGEPC. However, the finding that the cyclooxygenase inhibitor indomethacin enhanced AGEPC-stimulated cyclic AMP accumulation is a novel observation and suggests that some oxygenated derivative of the 5-lipoxygenase pathway is responsible for the increase in cyclic AMP. The evidence for the association of the spike in cyclic AMP and the 5-lipoxygenase is strengthened by the observation that the 5-lipoxygenase inhibitor U-60257 attenuates the AGEPC-induced spike in cyclic AMP. It should be noted that U-60257 does not antagonize LTB4-stimulated cyclic AMP accumulation and has no direct influence on the neutrophil adenylate cyclase. The final correlation of the spike in cyclic AMP and the 5-lipoxygenase is made by the fact that LTB4 itself stimulates cyclic AMP levels in intact neutrophils as well as the adenylate cyclase in cell homogenates. As is the case with AGEPC, the transient spike in cyclic AMP induced by LTB4 is coincident with the onset of neutrophil aggregation. However, it is clear that the spike in neutrophil cyclic AMP induced by AGEPC can be dissociated from neutrophil aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylglycerylether phosphorylcholine-(AGEPC) and leukotriene B4-stimulated cyclic AMP levels in human polymorphonuclear leukocytes. 632 44

The marine natural products manoalide and scalaradial are potent anti-inflammatory agents that inactivate the enzyme phospholipase A2 (PLA2) in vitro. To study the mechanism of inhibition of prostaglandin E2 (PGE2) production in human monocytes by manoalide and scalaradial, lipopolysaccharide (LPS)-induced prostaglandin biosynthesis and induction of prostaglandin H synthase (PGHS) were evaluated. LPS (10 ng/mL) and interleukin-1 beta (IL-1 beta, 50-1000 ng/mL) but not tumor necrosis factor alpha (TNF alpha, 300 ng/mL) induced the expression of the PGHS-2 isoform as determined by immunoblot analysis with a specific polyclonal antibody for PGHS-2. Manoalide and scalaradial (1-10 microM) inhibited LPS-induced endogeneous PGE2 production, reduced the LPS-induced PGHS activity, and reduced the expression of PGHS-2. Indomethacin [a PGHS inhibitor (0.01 to 0.1 microM)], zileuton [a 5-lipoxygenase inhibitor (3-10 microM)], and WEB-2806 [a platelet-activating factor (PAF) antagonist (30 microM)] did not affect the LPS-induced expression of PGHS-2 in human monocytes. These results suggest that modulation of lipid mediator production by manoalide or scalaradial may not be involved in the observed effects on the expression of PGHS-2. Manoalide and scalaradial also inhibited the release of IL-1 beta and TNF alpha from LPS-stimulated monocytes. Expression of PGHS-2 induced by either LPS or IL-1 beta was blocked by the IL-1 receptor antagonist (IL-1ra, 2 micrograms/mL) but not by rolipram, a phosphodiesterase IV inhibitor that inhibits TNF alpha but not IL-1 beta release. Similar to LPS, IL-1 beta-induced PGHS-2 expression was apparently not regulated by lipid mediators such as prostaglandins, leukotrienes or PAF as determined with specific inhibitors and antagonists. Scalaradial and to some extent manoalide were capable of blocking the IL-1 beta-induced expression of PHGS-2. These results indicate that IL-1 beta is the predominant cytokine responsible for the induction of PGHS-2 in the human monocyte. Furthermore, marine natural products such as scalaradial have novel effects on the IL-1 beta-mediated induction of PGHS-2 in human monocytes, which appears to be independent of effects on lipid mediator production.
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PMID:Regulation of prostaglandin H synthase 2 expression in human monocytes by the marine natural products manoalide and scalaradial. Novel effects independent of inhibition of lipid mediator production. 757 73

The pharmacological effects of N-[2-(4-(benzhydryloxy)piperidino)ethyl]-3-hydroxy-5-(3-pyridyl methoxy)-2- naphthamide (F-1322), a novel anti-asthmatic agent, was investigated in vitro. The results obtained were as follows: 1) In the isolated trachea of guinea pigs, F-1322 showed a markedly potent antagonistic action against the contraction induced by histamine, while it had little or no effect on 5-hydroxytryptamine-, acetylcholine-, leukotriene D4- or U-46619-induced contractions. 2) In rabbit platelets, F-1322 did not affect the platelet aggregation induced by platelet activating factor. 3) F-1322 significantly inhibited the thromboxane (TX) A2 synthetase (IC50 value: 1.7 x 10(-8) M) and 5-lipoxygenase (IC50 value: 9 x 10(-7) M) activities. 4) F-1322 had no effect on phospholipase A2, cyclooxygenase, Ca2+/calmodulin-dependent phosphodiesterase and phosphodiesterase activities. These in vitro studies suggest that the anti-asthmatic action of F-1322 is associated with histamine antagonism and an inhibitory action on TXA2 synthetase and 5-lipoxygenase activities.
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PMID:[Pharmacological profiles of F-1322, a novel anti-asthmatic agent. (1). Mechanisms of action]. 759 May 21

MK-886, a leukotriene biosynthesis inhibitor, which prevents the translocation and activation of 5-lipoxygenase, has been proposed as an effective drug for the treatment of inflammatory disorders, including psoriasis. In the present study, we investigated the effects of MK-886 on calmodulin as a potential target protein of anti-inflammatory drug activity, and on the proliferation of cultured human keratinocytes, a calmodulin-dependent cellular response with indicative value for antipsoriatic drug activity. Despite potent calmodulin-antagonistic activity in vitro, MK-886 failed to block cell proliferation in a human keratinocyte line, whereas trifluoperazine, a well characterized calmodulin antagonist with similar effects on calmodulin activity in our in vitro assays, inhibited cell proliferation in a dose-dependent manner. Further investigations on the mechanism of action revealed that, in contrast with trifluoperazine, calmodulin antagonism by MK-886 in vitro is likely to be mediated at the level of the allosteric calmodulin-recognition site of phosphodiesterase, rather than by binding to calmodulin itself. Therefore, our data do not conflict with the proposed role of calmodulin in the regulation of cell proliferation, but demonstrate that drug-induced antagonism of calmodulin, detected by inhibition of calmodulin-dependent enzymes in vitro, is not necessarily linked to antiproliferative activity in human keratinocytes.
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PMID:Potent antagonism of calmodulin activity in vitro, but lack of antiproliferative effects on keratinocytes by the novel leukotriene biosynthesis inhibitor MK-886. 766 39


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