Arachidonic acid products

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Metabotropic receptors, in contrast, create their effects by activating an intracellular G protein. The metabotropic receptors are monomers with seven transmembrane domains. The activated G protein, in turn, may activate an ion channel from an intracellular site. Alternately, G proteins work by activation or inhibition of enzymes that produce intracellular messengers. For example, activation of adenylate cyclase increases production of cyclic adenosine monophosphate (cAMP). Other effector mechanisms include activation of phospholipases, diacylglycerol, creation of inositol phosphates, and production of arachidonic acid products. Ultimately, these cascades can result in protein phosphorylation. 

Stredanska, S., Slugen, D., Stredansky, M., and Grego, J. 1993. Arachidonic acid production by Mortierella alpina grown on solid substrates. World J. Microbiol. Biotechnol., 9, 511-513. 

Figure 9.5. CYP epoxygenase- and hydroxylase-mediated metabolism of arachidonic acid. Products include biologically active EETs and HETEs. (Adapted from Seubert et al. Prostaglandins and Other Lipid Mediators 82, 50-59, 2007.)...

Lapetina EG. Regulation of arachidonic acid production role of phospholipase C and A2. Trends Pharmacol 1982 1I5-119... 

Once sensitivity has been established, that is, once hapten-specific IgE-producing B cells have been formed, exposure to even small amounts of hapten can induce a cascade of events that lead to immediate reactions, such as anaphylaxis (210). Briefly, preformed IgE antibodies to drug determinants recognize the hapten-carrier complex and fix to the surface of mast cells or basophils, triggering the release of a series of mediators, such as histamine, neutral proteases, biologically active arachidonic acid products, and cytokines. This ultimately leads to a clinical spectrum that ranges from a mUd local reaction to anaphylactic shock. 

For the reasons given above, agents that interfere with leukotriene synthesis or actions, are of great interest in relation to limiting inflammatory reactions. The sites amenable to pharmacological manipulation include (I) the upstream inhibition of arachidonic acid production from phospholipids (which is a rate-limiting step see PHOSPHOLIPASE inhibitors) (2) the inactivation of five-... 

The metabolites recovered from peaks I and II had different retention times on reverse-phase HPLC from arachidonic acid products formed by lipoxygenases. 

The interrelationship between the different arachidonic acid products, the prostaglandins, thromboxanes and leukotrienes, in the pathophysiology of human asthma is obviously complex, and extensive further studies are required to clarify the roles of these substances as well as of other mediators of the anaphylactic reaction. 

Ahem, T.J., Katoh, S. and Sada, E. (1983) Arachidonic acid production by the red alga Porphyridium cruentum. Physiol. Plant 16, 636-643. 

Ahern, T.J., Katoh, S. and Sada, E., 1983, Arachidonic acid production by the red alga Porphyridiura cruentum. Biotech, tc Bioeng., 25 1057-70. Donshak, A., Cohen, 2. 4t Richmond, A., 1985, The feasibility of mass cultivation of Porphyridiura, Biomass. 8 13-25. 

The bronchial epithelium is increasingly being shown to play a dynamic role in regulating the inflammation, repair, and remodeling process of asthma. It is well established as an important source of mediators including arachidonic acid products (15-HETE, PGE2), nitric oxide (NO) endothelins, cytokines (IL-ip, IL-5, IL-6, IL-11, GM-CSF, IL-16, IL-18) (93-98), chemokines (IL-8, Gro-a, MCP-1, MCP-3, RANTES, MIP-la, MIP-2, eotaxin, and eotaxin-2), and molecules involved in inflammation and repair. 

Mediators of both the infiammatoiy and fibrotic responses have been associated with exposure to oxidants. Similarly, mediator release after incubation of cells with silica and asbestos can be the result of oxygen-based free radicals catalyzed by iron associated with the mineral oxide (Fig. 1). The increase in arachidonic acid metabolism after exposures of cells to particles and fibers can result from the eooxidation of arachidonate by metal-catalyzed oxidants. This is a lipid peroxidation that can be mediated by free radical production by the dust (83). In support of an association between metal-catalyzed oxidant generation and arachidonic acid products, the release of LTB4 by alveolar macrophages can increase with the eoneentrations of iron complexed to the surface of silica and asbestos (84). Similarly, the eellular release of eytokines postulated to participate in the infiammatory and fibrotic responses ean be associated with exposures to metal-dependent radicals (see Fig. 1). TNF-a produetion by alveolar macrophages after mineral oxide exposure can be inhibited by both the metal chelator deferoxamine and hydroxyl radical scavengers (74). The release of other cytokines pertinent to silica and asbestos exposure ean also be responsive to oxidative stress (85,86). The release of these pertinent mediators after dust exposures is likely to be controlled by oxidant-sensitive promoters such as nuclear factor (NF)-kB (87). After exposure to silica and asbestos, NF-kB can function as a promoter... 

Rather than being a maladaptive response, the inflammation initiated and coordinated by arachidonic acid products and cytokines after exposure to mineral oxides is absolutely essential for the survival of the host. The iron was initially complexed to the dust with a labile or reactive coordination site available. Consequently, the metal was capable of oxidant generation and injury to host tissues. After reduction by superoxide produced by NADPH oxidoreductase in the neutrophil, reaction with lactoferrin released by the neutrophil (108), and deposition in ferritin of the reticuloendothelial system (109), the iron is rendered catalytically less active. 

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