Eicosanoid analogs

The absolute stereochemistries for both compounds were determined by CD analysis of the p-bromobenzoate derivatives. Two other eicosanoids were also isolated from whole animals [198], The trihydroxylated oxylipin 8jR,11S,12R-trihydroxyeicosa-5Z,9 ,14Z,17Z-tetraenoic acid (trioxilin A4,150) was detected in, or isolated from, five starfish species P. miniata, Dermasterias imbricata, Pycnopodia helianthoides, Culcita novaeguinea, and Nardoa tubercolata. Its structure was determined by H and 13C NMR and FAB-MS analyses of the natural product and of an acetonide derivative. The co6 analog of this compound (151) was isolated only from P. helianthoides. The relative stereochemistry in these metabolites (150, 151) was established from a comparison of NMR shifts with malyngic acid, a trihydroxylated C18 compound isolated from Lyngbya majuscula, while the absolute stereochemistry was proposed on the basis of the earlier isolation of 8R-HETE from P. miniata. 

The treatment of neuronal cultures with glutamate and its analogs results in a dose-dependent increase in CPLA2, COX, and LOX activities and arachidonic acid, eicosanoids and ROS release (Dumuis et al., 1988 Lazarewicz et al., 1990 Farooqui et al., 2003b Adams et al., 1996 Manev et al., 1998). Glutamate recep-... 

The first identified cannabinoid receptor subtype, CB was cloned and demonstrated to have an amino acid sequence consistent with a tertiary structure typical of the seven transmembrane-spanning proteins that are coupled to G proteins. In addition to being found in the central nervous system, mRNA for CB has also been identified in testes. The central nervous system responses to cannabinoid compounds are believed to be mediated exclusively by CB, inasmuch as CB2 transcripts could not be found in brain tissue by either Northern analysis or in situ hybridization studies. CBj transduces signals in response to central-nervous-system-active constituents of C. sativa as well as synthetic bicyclic and tricyclic cannabinoid analogs, aminoalkylindole, and eicosanoid cannabimimetic compounds. CB is coupled to G, to inhibit adenylate cyclase activity and to a pertussis-sensitive G protein to regulate Ca2+ currents. 

Analogous to the discovery of endogenous opiates, isolation of cannabinoid receptors provided the appropriate tool to isolate an endogenous cannabimimetic eicosanoid, anandamide, from porcine... 

The drug most commonly used in patients who do not respond to sildenafil is alprostadil, a PGE1 analog (see Chapter 18 The Eicosanoids Prostaglandins, Thromboxanes, Leukotrienes, Related Compounds) that can be injected directly into the cavernosa or placed in the urethra as a mini suppository, from which it diffuses into the cavemosal tissue. Phentolamine can be used by injection into the cavernosa. These drugs will cause erection in most men who do not respond to sildenafil. 

Several approaches have been used in the clinical application of eicosanoids. First, stable oral or parenteral long-acting analogs of the naturally occurring prostaglandins have been developed. 

The first step in the formation of eicosanoid mediators consists in the release of the precursor fatty acids from the membrane phospholipids. This release may happen along several possible metabolic routes (Figure 12.2a). The major physiological mechanism of release consists in the activation of a cytosolic phospholipase A2 (CPLA2) by Ca in response to an extracellular signal. CPLA2 then attaches to the nuclear (and probably ER) membranes, which appear to be the major reservoir of araehidonie acid and its analogs. 

The formation of the most important eicosanoid derivatives of arachidonic acid and its analogs is initiated by cyclooxygenases (Cox) and lipoxygenases (Lox) ... 

The little success of search for prostaglandins in plant tissues is probably not accidental. To evaluate the perspectives of search for eicosanoids or their analogs it is necessary to take into account the relative abundance of different poly-enoic fatty acids in plants. Most plants, according to all available data, are free of metabolic precursors of eicosanoids,... 

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