RESUMEN
The usage of cisplatin, a highly potent chemotherapeutic, is limited by its severe nephrotoxicity. Arachidonic acid (ARA)-derived epoxyeicosatrienoic acids (EETs) and soluble epoxide hydrolase (sEH) inhibitors were shown to ameliorate this dose-limiting side effect, but both approaches have some pharmacological limitations. Analogues of EETs are an alternative avenue with unique benefits, but the current series of analogues face concerns regarding their structure and mimetic functionality. Hence, in this study, regioisomeric mixtures of four new ARA alkyl ethers were synthesized, characterized, and assessed as EET analogues against the concentration- and time-dependent toxicities of cisplatin in porcine proximal tubular epithelial cells. All four ether groups displayed bioisostere activity, ranging from marginal for methoxy- (1), good for n-propoxy- (4), and excellent for ethoxy- (2) and i-propoxy- (3). Compounds 2 and 3 displayed cytoprotective effects comparable to that of an EET regioisomeric mixture (5) against high, acute cisplatin exposures but were more potent against low to moderate, chronic exposures. Compounds 2 and 3 (and 5) acted through stabilization of the mitochondrial transmembrane potential and attenuation of reactive oxygen species, leading to reduced phosphorylation of mitogen-activated protein kinases p38 and JNK and decreased activation of caspase-9 and caspase-3. This study demonstrates that alkoxy- groups are potent and more metabolically stable bioisostere alternatives to the epoxide within EETs that enable sEH-independent activity. It also illustrates the potential of ether-based mimics of EETs and other epoxy fatty acids as promising nephroprotective agents to tackle the clinically relevant side effect of cisplatin without compromising its antineoplastic function.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Caspasa 3/metabolismo , Caspasa 9/metabolismo , Células Epiteliales/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Antineoplásicos/toxicidad , Células Cultivadas , Cisplatino/antagonistas & inhibidores , Cisplatino/toxicidad , Relación Dosis-Respuesta a Droga , Humanos , Túbulos Renales Proximales/efectos de los fármacos , Mitocondrias/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estructura Molecular , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , PorcinosRESUMEN
COX metabolites of 8,9-EET, previously observed as potent mitogenic lipid mediators, were synthesized for the first time by using two synthetic approaches. These synthetic materials allow for structural confirmation of COX metabolites of 8,9-EET and further study of their biological roles.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ciclooxigenasa 2/metabolismo , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/metabolismo , Ciclooxigenasa 2/química , Estructura Molecular , EstereoisomerismoRESUMEN
Epoxyeicosatrienoic acids (EETs) are endothelium-derived metabolites of arachidonic acid. They relax vascular smooth muscle by membrane hyperpolarization. These actions are inhibited by the EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EE5ZE). We synthesized 20-(125)iodo-14,15-EE5ZE (20-(125)I-14,15-EE5ZE), a radiolabeled EET antagonist, and characterized its binding to cell membranes. 14,15-EET (10(-9)-10(-5)M) caused a concentration-related relaxation of the preconstricted bovine coronary artery and phosphorylation of p38 in U937 cells that were inhibited by 20-(125)I-14,15-EE5ZE. Specific 20-(125)I-14,15-EE5ZE binding to U937 cell membranes reached equilibrium within 5 min and remained unchanged for 30 min. The binding was saturable and reversible, and it exhibited K(D) and B(max) values of 1.11 +/- 0.13 nM and 1.13 +/- 0.04 pmol/mg protein, respectively. Guanosine 5'-O-(3-thio)triphosphate (10 muM) did not change the binding, indicating antagonist binding of the ligand. Various EETs and EET analogs (10(-10)-10(-5)M) competed for 20-(125)I-14,15-EE5ZE binding with an order of potency of 11,12-EET = 14,15-EET > 8,9-EET = 14,15-EE5ZE > 15-hydroxyeicosatetraenoic acid = 14,15-dihydroxyeicosatrienoic acid. 8,9-Dihydroxyeicosatrienoic acid and 11-hydroxyeicosatetraenoic acid did not compete for binding. The soluble and microsomal epoxide hydrolase inhibitors (1-cyclohexyl-3-dodecyl-urea, elaidamide, and 12-hydroxyl-elaidamide) and cytochrome P450 inhibitors (sulfaphenazole and proadifen) did not compete for the binding. However, two cytochrome P450 inhibitors, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) and miconazole competed for binding with K(i) of 1558 and 315 nM, respectively. Miconazole and MS-PPOH, but not proadifen, inhibited 14,15-EET-induced relaxations. These findings define an EET antagonist's binding site and support the presence of an EET receptor. The inhibition of binding by some cytochrome P450 inhibitors suggests an alternative mechanism of action for these drugs and could lead to new drug candidates that target the EET binding sites.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Membrana Celular/metabolismo , Compuestos Epoxi/farmacología , Ácido 8,11,14-Eicosatrienoico/antagonistas & inhibidores , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Sitios de Unión , Western Blotting , Bovinos , Membrana Celular/efectos de los fármacos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Inhibidores Enzimáticos del Citocromo P-450 , Relación Dosis-Respuesta a Droga , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos Epoxi/síntesis química , Compuestos Epoxi/química , Humanos , Radioisótopos de Yodo , Ligandos , Fosforilación , Células U937 , Vasodilatación/efectos de los fármacos , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
All-cis-14,15-epoxyeicosa-5,8,11-trienoic acid (14,15-EET) is a labile, vasodilatory eicosanoid generated from arachidonic acid by cytochrome P450 epoxygenases. A series of robust, partially saturated analogues containing epoxide bioisosteres were synthesized and evaluated for relaxation of precontracted bovine coronary artery rings and for in vitro inhibition of soluble epoxide hydrolase (sEH). Depending upon the bioisostere and its position along the carbon chain, varying levels of vascular relaxation and/or sEH inhibition were observed. For example, oxamide 16 and N-iPr-amide 20 were comparable (ED(50) 1.7 microM) to 14,15-EET as vasorelaxants but were approximately 10-35 times less potent as sEH inhibitors (IC(50) 59 and 19 microM, respectively); unsubstituted urea 12 showed useful activity in both assays (ED(50) 3.5 microM, IC(50) 16 nM). These data reveal differential structural parameters for the two pharmacophores that could assist the development of potent and specific in vivo drug candidates.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Epóxido Hidrolasas/antagonistas & inhibidores , Compuestos Epoxi/síntesis química , Vasodilatación/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Bovinos , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/fisiología , Compuestos Epoxi/química , Compuestos Epoxi/farmacología , Humanos , Técnicas In Vitro , Contracción Isométrica/efectos de los fármacos , Proteínas Recombinantes/antagonistas & inhibidores , Solubilidad , Estereoisomerismo , Relación Estructura-Actividad , Vasodilatadores/síntesis química , Vasodilatadores/química , Vasodilatadores/farmacologíaRESUMEN
Glomerular dysfunction and proteinuria characterize focal segmental glomerulosclerosis (FSGS) associated with chronic kidney disease. FSGS is resistant to treatment and a circulating permeability factor (FSPF) frequently causes post-renal transplantation recurrence. In order to explore the role of 5,6-, 8,9-, 11,12- and 14,15-epoxyeicosatrienoic acids (EETs), we determined their effect on FSPF-induced increase in glomerular albumin permeability (P alb) using an in vitro assay. Exogenous 8,9-EET (1-1000 nM) dose-dependently prevented the FSPF-induced increase in P alb. The other three EET regioisomers, 8,9-EET metabolite, 8,9-dihydroxyeicosatrienoic acid and unrelated 11,14-eicosadienoic acid (100 nM each) were not effective suggesting specificity of the observed glomerular protection by 8,9-EET. Synthetic analogs of 8,9-EET containing one double bond antagonized the effect of 8,9-EET on the FSPF-induced increase in P alb. Analogs containing two double bonds did not antagonize the effect of 8,9-EET and significantly blocked the FSPF-induced increase in P alb. These novel findings suggest a unique protective role for 8,9-EET in the glomerulus. Stable analogs of 8,9-EET may be valuable in developing effective management/treatment of glomerular dysfunction.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/metabolismo , Vasodilatadores/farmacología , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Bovinos , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Humanos , Técnicas In Vitro , Masculino , Permeabilidad/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Albúmina Sérica/metabolismo , Estereoisomerismo , Relación Estructura-Actividad , Vasodilatadores/síntesis química , Vasodilatadores/químicaRESUMEN
[reaction: see text] The title compound 1 was obtained via methyl ester 2, which was synthesized in four steps from an isomeric 11,14,15-triol ester 5. In the key step, Boc orthoformate 9 was treated with TMS triflate to initiate intramolecular nucleophilic substitution with allylic transposition, forming cyclic carbonates 10 and 11.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Vasodilatadores/síntesis química , Ácido 8,11,14-Eicosatrienoico/síntesis química , Carbonatos/química , Catálisis , Ésteres , Estructura Molecular , Propanoles/químicaRESUMEN
A novel, facile synthesis of 5,6-trans-epoxyeicosatrienoic acid (5,6-trans-EET) from 5,6-trans-arachidonic acid by iodolactonization and alkaline de-iodation is described along with characterization by mass spectrometry (LC-MS, negative ions) and NMR and comparison with 5,6-cis-EET.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Espectrometría de Masa por Ionización de Electrospray , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/aislamiento & purificación , Ácido Araquidónico/metabolismo , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , EstereoisomerismoRESUMEN
A series of 11,12-EET analogues were synthesized and compared using a human endothelial cell based TNF-alpha-induced VCAM-1 expression assay. The resulting data were used to map a putative recognition/binding domain for 11,12-EET.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacología , Factor de Necrosis Tumoral alfa/farmacología , Molécula 1 de Adhesión Celular Vascular/genética , Ácido 8,11,14-Eicosatrienoico/síntesis química , Animales , Sitios de Unión , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/fisiología , Humanos , Estructura Molecular , Relación Estructura-Actividad , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Molécula 1 de Adhesión Celular Vascular/química , Molécula 1 de Adhesión Celular Vascular/efectos de los fármacosRESUMEN
Nitric oxide (NO)-derived species could potentially react with arachidonic acid to generate novel vasoactive metabolites. We studied the reaction of arachidonic acid with nitrogen dioxide (NO2), a free radical that originates from NO oxidation. The reaction mixture contained lipid products that relaxed endothelium-removed bovine coronary arteries. Relaxation to the lipid mixture was inhibited approximately 20% by indomethacin and approximately 70% by a soluble guanylate cyclase (sGC) inhibitor (ODQ). Thus, novel lipid products, which activate sGC presumably through a mechanism involving NO, appeared to have contributed to the observed vasorelaxation. Lipids that eluted at 9 to 12 min during high-performance liquid chromatography fractionation accounted for about one-half of the vasodilator activity in the reaction mixture, which was inhibited by ODQ. Lipid products in fractions 9 to 12 were identified by electrospray tandem mass spectrometry to be eight isomers having molecular weight of 367 and a fragmentation pattern indicative of arachidonic acid derivatives containing nitro and hydroxy groups and consistent with the structures of vicinal nitrohydroxyeicosatrienoic acids. These lipids spontaneously released NO (183 +/- 12 nmol NO/15 min/micromol) as detected by head space/chemiluminescence analysis. Mild alkaline hydrolysis of total lipids extracted from bovine cardiac muscle followed by isotopic dilution gas chromatography/mass spectrometry analysis detected basal levels of nitrohydroxyeicosatrienoic acids (6.8 +/- 2.6 ng/g tissue; n = 4). Thus, the oxidation product of NO, NO2, reacts with arachidonic acid to generate biologically active vicinal nitrohydroxyeicosatrienoic acids, which may be important endogenous mediators of vascular relaxation and sGC activation.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido Araquidónico/química , Lípidos/síntesis química , Lípidos/farmacología , Donantes de Óxido Nítrico/síntesis química , Donantes de Óxido Nítrico/farmacología , Dióxido de Nitrógeno/química , Nitroparafinas/síntesis química , Nitroparafinas/farmacología , Vasodilatadores/síntesis química , Vasodilatadores/farmacología , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Bovinos , Cromatografía Líquida de Alta Presión , Vasos Coronarios/efectos de los fármacos , Vasos Coronarios/metabolismo , Técnicas In Vitro , Metabolismo de los Lípidos , Mediciones Luminiscentes , Masculino , Espectrometría de Masas , Contracción Muscular/efectos de los fármacos , Ratas , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
A novel analog of hepoxilin A3 has been chemically synthesized in which the 11,12-epoxide group has been altered to a thiirano group. This has been accomplished through allylic rearrangement of unnatural (11 R, 12 R)-hepoxilin B3 under Mitsunobu conditions, first into unnatural (11 R, 12 R)-hepoxilin A3, followed by conversion of this compound with inversion of the epoxide centers into the thiirano-hepoxilin A3 having the natural 11 S, 12 S configuration. We also report herein evidence showing that thiirano-hepoxilin A3 raises intracellular calcium concentrations in intact human neutrophils.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Calcio/metabolismo , Neutrófilos/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/química , Ácido 8,11,14-Eicosatrienoico/farmacología , Relación Dosis-Respuesta a Droga , Humanos , Espectroscopía de Resonancia Magnética , Conformación Molecular , Neutrófilos/metabolismoRESUMEN
Epoxyeicosatrienoic acids (EETs), normally present in brain and blood, appear to be released from atherosclerotic vessels in large amounts. Once intravascular, EETs can constrict renal arteries in vivo and dilate cerebral and coronary arteries in vitro. Whether EETs in blood will alter cerebral blood flow (CBF) in vivo is unknown. In the present study, the chemical synthesis of four EET regioisomers was optimized, and their identity and structural integrity established by chromatographic and mass spectral methods. The chemically labile EETs were converted to a sodium salt, complexed with albumin, and infused into anesthetized rats via the common carotid. The objective was to test whether sustained, high levels of intravascular EETs alter CBF. The CBF (cortical H2 clearance) was measured before and 30 min after the continuous infusion of 14,15- (n = 5), 11,12- (n = 5), 8,9- (n = 7) and 5,6-EET (unesterified or as the methyl ester, n = 5 for each). Neither the CBF nor the systemic blood pressure was affected by EETs. Because the infusions elevated the plasma concentrations of EETs about 700-fold above normal levels (1.0 nM), it is unlikely that EETs released from atherosclerotic vessels will alter CBF.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Circulación Cerebrovascular/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/administración & dosificación , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Cromatografía Líquida de Alta Presión , Cromatografía de Gases y Espectrometría de Masas , Infusiones Intravenosas , Masculino , Ratas , Ratas WistarRESUMEN
This article reviews published evidence describing the enzymatic and nonenzymatic formation and the routes of metabolism of the hepoxilins. Also treated are the major approaches used for the chemical synthesis of these compounds and for some of their analogs.
Asunto(s)
Leucotrienos/metabolismo , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/metabolismo , Animales , Estabilidad de Medicamentos , Leucotrienos/síntesis química , Estructura MolecularRESUMEN
This review is intended to summarize the biological actions of the hepoxilins reported to date. These actions appear to have, as their basis, changes in intracellular concentrations of ions including calcium and potassium ions as well as changes in second messenger systems. Recent evidence suggests that the biological actions of the hepoxilins may be receptor-mediated as indicated from data showing the existence of hepoxilin-specific binding proteins in the human neutrophil. Such evidence also implicates the association of G-proteins both in hepoxilin-binding as well as in hepoxilin action. The potential use of stable analogs of the hepoxilins is discussed as well as the directions in which this area is heading.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/metabolismo , Ácido 8,11,14-Eicosatrienoico/farmacología , Animales , Cationes , Humanos , Sistemas de Mensajero SecundarioRESUMEN
The total syntheses of the 5- and 6-fluoro derivatives of 5,8,14-eicosatrienoic (ETA) and arachidonic (AA) acids are described. The fluorinated double bond was introduced using (E)-1,4-dihydroxy-2-fluoro-2-butene obtained through diisobutylaluminium hydride reduction of dimethylfluoromaleate. Recently, 5-fluoro and 6-fluoro arachidonic acids (5-F-AA and 6-F-AA) were found to be effective inhibitors of 5-lipoxygenase in vitro (Nave, J. F.; Jacobi, D.; Gaget, C.; Dulery, B.; Ducep, J. B., Biochem. J. 1991, 278, 549). The effect of these compounds on leukotriene C4 (LTC4) production by intact cells was investigated. Mouse peritoneal macrophages were cultured in the presence of 5-F-AA or 6-F-AA under conditions where AA was found to be efficiently incorporated into cellular phospholipids. Following stimulation with zymosan, macrophages treated with 20 microM 6-F-AA released 30 to 35% less LTC4 than control cells. In contrast, macrophages treated with 20 microM 5-F-AA released 1.5 to 1.8 times more LTC4 than control cells. In competition experiments with [14C]-AA, 5-F-AA modified the distribution profile of [14C]-AA within the various classes of lipids in a way similar to AA. 6-F-AA had a distinct behaviour, producing a more important incorporation of [14C]-AA into the neutral lipid fraction at the expense of the phospholipid fraction than AA and 5-F-AA. 6-F-AA is expected to be an important tool in further studies of the arachidonic acid pathway in vivo.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácido 8,11,14-Eicosatrienoico/farmacología , Ácidos Araquidónicos/síntesis química , Ácidos Araquidónicos/farmacología , Leucotrieno C4/biosíntesis , Macrófagos Peritoneales/efectos de los fármacos , Ácido 8,11,14-Eicosatrienoico/química , Animales , Ácidos Araquidónicos/química , Fluoruros/síntesis química , Fluoruros/química , Fluoruros/farmacología , Técnicas In Vitro , Metabolismo de los Lípidos , Lípidos/química , Macrófagos Peritoneales/metabolismo , Masculino , Ratones , Estructura MolecularRESUMEN
Ethyl 5,8,11,14-eicosatetraenoate-19,19,20,20-d4 and ethyl 8,11,14-eicosatrienoate-19,19,20,20-d4 were synthesized by Grignard coupling of the methanesulfonyl ester of 2,5-undecadiyn-1-ol-10,10,11,11-d4 with 5,8-nonadiynoic acid and 8-nonynoic acid, respectively. The coupled products upon Lindlar reduction, followed by the preparation of their ethyl esters, yielded deuteriated ethyl arachidonate and ethyl dihomo-gamma-linolenate, which were completely characterized by 13C and 1H nuclear magnetic resonance and mass spectral analysis.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácidos Araquidónicos/síntesis química , Ácido 8,11,14-Eicosatrienoico/síntesis química , Cromatografía de Gases , Cromatografía de Gases y Espectrometría de Masas , Espectroscopía de Resonancia MagnéticaRESUMEN
Incubation of (8R)- and (8S)-[1-14C]hepoxilin A3 [where hepoxilin A3 is 8-hydroxy-11,12-epoxyeicosa-(5Z,9E,14Z)-trienoic acid] and glutathione with homogenates of rat brain hippocampus resulted in a product that was identified as the (8R) and (8S) diastereomers of 11-glutathionyl hepoxilin A3 by reversed-phase high performance liquid chromatographic comparison with the authentic standard made by total synthesis. Identity was further confirmed by cleavage of the isolated product with gamma-glutamyltranspeptidase to yield the corresponding cysteinylglycinyl conjugate that was identical by reversed-phase high performance liquid chromatographic analysis with the enzymic cleavage product derived from the synthetic glutathionyl conjugate. The glutathionyl and cysteinylglycinyl conjugate are referred to as hepoxilin A3-C and hepoxilin A3-D, respectively, by analogy with the established leukotriene nomenclature. Formation of hepoxilin A3-C was greatly enhanced with a concomitant decrease in formation of the epoxide hydrolase product, trioxilin A3, when the epoxide hydrolase inhibitor trichloropropene oxide was added to the incubation mixture demonstrating the presence of a dual metabolic pathway in this tissue involving hepoxilin epoxide hydrolase and glutathione S-transferase processes. Hepoxilin A3-C was tested using intracellular electrophysiological techniques on hippocampal CA1 neurons and found to be active at concentrations as low as 16 nM in causing membrane hyperpolarization, enhanced amplitude and duration of the post-spike train afterhyperpolarization, a marked increase in the inhibitory postsynaptic potential, and a decrease in the spike threshold. These findings suggest that these products in the hepoxilin pathway of arachidonic acid metabolism formed by the rat brain may function as neuromodulators.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/metabolismo , Ácidos Grasos Insaturados/metabolismo , Glutatión/metabolismo , Hipocampo/metabolismo , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/síntesis química , Animales , Radioisótopos de Carbono , Epóxido Hidrolasas/antagonistas & inhibidores , Potenciales Evocados , Hipocampo/fisiología , Indicadores y Reactivos , Masculino , Ratas , Ratas Endogámicas , Tricloroepoxipropano/farmacologíaRESUMEN
8Z,11Z,14Z-Eicosatriene-5-ynoic acid and its tritium-labelled analogue, [5,6-3H]arachidonic acid, have been synthesized on the basis of acetylenic compounds. [5,6-3H]Arachidonic acid has been used as substrate for the enzymatic synthesis of [5,6-3H]PGE2 and [5,6-3H]PGF2 alpha.
Asunto(s)
Ácido 8,11,14-Eicosatrienoico/síntesis química , Ácidos Araquidónicos/metabolismo , Ácidos Grasos Insaturados/síntesis química , Prostaglandinas E/metabolismo , Prostaglandinas F/metabolismo , Ácido 8,11,14-Eicosatrienoico/análogos & derivados , Ácido 8,11,14-Eicosatrienoico/metabolismo , Ácido Araquidónico , Fenómenos Químicos , Química , Dinoprost , Dinoprostona , Prostaglandinas E/biosíntesis , Prostaglandinas F/biosíntesisRESUMEN
Two isomeric icosatrienoic acids with double bonds at positions 5,8,14 and 5,11,14 and their 1-14C- and acetylenic analogues were prepared. The syntheses and characterization of these acids are described.