Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P15088 (mast cell)
 14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have synthesized a series of 3-deoxy-3-heteromethyl derivatives of L-alpha-phosphatidyl-D-myo-inositol as part of our effort to develop specific, reversible inhibitors of phosphoinositide (PI) 3-kinase. Among various derivatives examined, phosphatidyl-D-3-deoxy-3-aminomethyl-myo-inositol displays the highest potency in inhibiting PI 3-kinase both in vitro and in cells. It effectively suppressed antigen-stimulated degranulation in mast cells (IC(50), 17 microM), suggesting a potential application of this PI 3-kinase inhibitor as a mast cell-stabilizing agent.
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PMID:Synthesis and biological evaluation of L-alpha-phosphatidyl-D-3-deoxy-3-heteromethyl-myo-inositols as phosphoinositide 3-kinase inhibitors. 1171 Dec 92

The antigen-induced release of histamine from sensitized guinea pig mast cells was dose-dependently reduced by endogenous (2-arachidonylglycerol; 2AG) and exogenous [(1R,3R,4R)-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-4-(3-hydroxypropyl)cyclohexan-1-ol (CP55,940)] cannabinoids. The inhibitory action afforded by 2AG and CP55,940 was reversed by N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl]5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3-carboxamide (SR144528), a selective cannabinoid 2 (CB(2)) receptor antagonist, and left unchanged by the selective CB(1) antagonist N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM251). The inhibitory action of 2AG and CP55,940 was reduced by the unselective nitric-oxide synthase (NOS) inhibitor N-monomethyl-L-arginine methylester (l-NAME) and reinstated by L-arginine, the physiological substrate. The inhibitory action of 2AG and CP55,940 was also reduced by the unselective cyclooxygenase (COX) inhibitor indomethacin and the selective COX-2 blocker rofecoxib. Both 2AG and CP55,940 significantly increased the production of nitrite from mast cells, which was abrogated by L-NAME and N-(3-(aminomethyl)benzyl)acetamidine (1400W), a selective inducible NOS (iNOS) inhibitor. Nitrite production consistently paralleled a CP55,940-induced increase in the expression of iNOS protein in mast cells. Both 2AG and CP55,940 increased the generation of prostaglandin E(2) from mast cells, which was abrogated by indomethacin and rofecoxib and parallel to the CP55,940-induced expression of COX-2 protein. Mast cell challenge with antigen was accompanied by a net increase in intracellular calcium levels. Both cannabinoid receptor ligands decreased the intracellular calcium levels, which were reversed by SR144528 and l-NAME. In unstimulated mast cells, both ligands increased cGMP levels. The increase was abrogated by SR144528, l-NAME, indomethacin, and rofecoxib. Our results suggest that 2AG and CP55,940 decreased mast cell activation in a manner that is susceptible to a CB(2) receptor antagonist and to inhibition of nitric oxide and prostanoid pathways.
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PMID:The endocannabinoid 2-arachidonylglycerol decreases the immunological activation of Guinea pig mast cells: involvement of nitric oxide and eicosanoids. 1518 70

beta-Tryptases are mast cell-derived serine proteases that are enzymatically active in the form of an oligomer consisting of four subunits each with trypsin-like activity. The active-site clefts, which are directed toward the central pore of the tetramer, form spatial arrays of four negatively charged S1 binding pockets. Therefore, dibasic inhibitors of appropriate geometry can bind in a bivalent fashion to neighboring subunits. We have recently identified a potent bivalent inhibitor (K(i)=18 nM), based on the bifunctional scaffold cyclo-(-D-Asp-L-Asp-) and the arginine mimetic dl-3-aminomethyl-phenylalanine methyl ester as a ligand for S1 pockets that takes advantage of the this unique tetrameric geometry. To generate an affinity matrix, the bivalent ligand was modified and immobilized on a Sepharose matrix by use of the PEG derivative Jeffamine ED 900 as spacer. This matrix selectively recognizes and binds beta-tryptase from crude protein mixtures and thus is useful as a geometry-driven means of isolating and purifying human mast cell tryptases.
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PMID:Affinity chromatography of tryptases: design, synthesis and characterization of a novel matrix-bound bivalent inhibitor. 1559 13

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.
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PMID:Structure based design of 4-(3-aminomethylphenyl)piperidinyl-1-amides: novel, potent, selective, and orally bioavailable inhibitors of betaII tryptase. 1578 96

Rats breathing 10% O2 show a rapid and widespread systemic microvascular inflammation that results from nitric oxide (NO) depletion secondary to increased reactive O2 species (ROS) generation. The inflammation eventually resolves, and the microcirculation becomes resistant to more severe hypoxia. These experiments were directed to determine the mechanisms underlying this microvascular acclimatization process. Intravital microscopy of the mesentery showed that after 3 wk of hypoxia (barometric pressure ~380 Torr; partial pressure of inspired O2 ~68-70 Torr), rats showed no evidence of inflammation; however, treatment with the inducible NO synthase (iNOS) inhibitor L-N6-(1-iminoethyl) lysine dihydrochloride led to ROS generation, leukocyte-endothelial adherence and emigration, and increased vascular permeability. Mast cells harvested from normoxic rats underwent degranulation when exposed in vitro to monocyte chemoattractant protein-1 (MCP-1), the proximate mediator of mast cell degranulation in acute hypoxia. Mast cell degranulation by MCP-1 was prevented by the NO donor spermine-NONOate. MCP-1 did not induce degranulation of mast cells harvested from 6-day hypoxic rats; however, pretreatment with either the general NOS inhibitor L-NG-monomethyl arginine citrate or the selective iNOS inhibitor N-[3-(aminomethyl) benzyl] acetamidine restored the effect of MCP-1. iNOS was demonstrated in mast cells and alveolar macrophages of acclimatized rats. Nitrate + nitrite plasma levels decreased significantly in acute hypoxia and were restored after 6 days of acclimatization. The results support the hypothesis that the microvascular acclimatization to hypoxia results from the restoration of the ROS/NO balance mediated by iNOS expression at key sites in the inflammatory cascade.NEW & NOTEWORTHY The study shows that the systemic inflammation of acute hypoxia resolves via an inducible nitric oxide (NO) synthase-induced restoration of the reactive O2 species/NO balance in the systemic microcirculation. It is proposed that the acute systemic inflammation may represent the first step of the microvascular acclimatization process.
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PMID:Acclimatization of the systemic microcirculation to alveolar hypoxia is mediated by an iNOS-dependent increase in nitric oxide availability. 2830 6