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The effect of derivatives of arachidonic and docosahexaenoic acids on AMPA receptors in Purkinje cells from the rat cerebellum was studied using the patch-clamp electrophysiological method. It was shown that derivatives of arachidonic acid-arachidonoyl dopamine and docosahexaenoic acid-docosahexaenoyl dopamine and ester of docosahexaenoic acid with ethylene glycol in nanomolar concentrations effectively potentiated the ionic currents caused by activation of AMPA receptors of kainic acid. Ester of docosahexaenoic acid with nitroethylene glycol blocked AMPA receptors, and anandamide (ethanolamide of arachidonic acid) was not effective. A behavioral test showed that docosahexaenoyl dopamine in doses of 0.1-20 mg/kg had no effect on the learning and memory abilities of the animals tested.

Glycerol esters 1,3-dinitrates of the cyclooxygenase metabolites of natural prostaglandin 2-arachidonoylglycerol, an endogenous ligand of cannabinoid receptors, were synthesized for the first time. Four methods of synthesis of these esters were developed via the activation of a carboxyl group and their chemical and pharmacological properties were investigated. The esters exhibit a more selective pharmacological spectrum of activities in comparison with the corresponding natural prostaglandins: some types of myotropic activity were enhanced, while others were loosened. 1,3-dinitroglycerol esters act as vasodilators, whereas the majority of natural prostaglandins act as vasoconstrictors. The observed changes result from the introduction of an NO-releasing fragment into prostaglandin molecule.

O-Nitration of the allylic hydroxyl group in prostaglandins and the synthesis of 15-O-nitrates of 11-deoxyprostaglandin E1 and its methyl ester are described for the first time.

A series of six new synthetic dinitroglycerol esters of fatty acids on the human platelet aggregation was studied in vitro. Inclusion of the dinitroglycerol moiety into the molecule of arachidonic acid deprived this acid from pro-aggregant activity. All six compounds produced moderate (dose-dependent) inhibition of the platelet aggregation process induced by arachidonic acid (1 x 10(-3) M). Platelet aggregation was most significantly affected by dinitroglycerol esters of arachidonic and docosahexaenoic acids. This is probably explained by the influence of these esters on the oxidative metabolism of arachidonic acid to eicosanoids playing the role of proaggregants. In the presence of vessel wall (rat aorta fragments), dinitroglycerol esters of arachidonic and docosahexaenoic acids incubated with platelets (5 min, 37 degrees C) significantly reduced their aggregation induced by arachidonic acid (1 x 10(-3) M) or docosahexaenoic acid (1 x 10(-5) M) under the conditions of endothelial cyclooxygenase suppressed by acetylsalicylic acid (10 mg/ml). The pronounced antiaggregant effect of the synthetic dinitroglycerol esters studied is probably related to their ability to act as NO donors suppressing the activity of thrombocytes (provided that the NO production activity is present in the system).

The interaction of organic nitrates (nitroethyleneglycol, dinitroglycerol, and their esters with arachidonic acid) with oxyhemoglobin and methemoglobin has been studied. Addition of nitroethyleneglycol and dinitroglycerol to oxyhemoglobin is accompanied by a modest but significant increase in oxidation rate of the heme protein to the high-spin ferri-form--methemoglobin. Arachidonoylglycerol dinitrate exerts a similar but more pronounced effect on hemoglobin: a molar excess of this dinitrate induces the transformation of a significant portion of oxyhemoglobin to methemoglobin, whereas arachidonoylnitroethyleneglycol is inactive. Arachidonoylglycerol dinitrate also induces changes in the spectral characteristics of methemoglobin; this may be due to disintegration of the methemoglobin with the loss of heme. The data demonstrate that some organic nitrates can interact with hemoglobin; this should be taken into account when using the oxyhemoglobin technique for measuring nitric oxide generation from these compounds.

(+/-)-15-Fluoro-11,15-dideoxyprostaglandin E1 and its methyl and ethyl esters were synthesized. Dehydroxyfluorination reaction (+/-)-11-deoxyprostaglandin E1 esters with various reagents based on SF4 was studied. Along with the target 15-fluorides (mixtures of alpha- and beta-epimers), products of allylic shift and dehydration in a ratio dependent on the fluorination agent were shown to be formed. With a morpholinotrifluorosulfuran-tris(morpholine)sulfonium trimethyldifluorosilicate mixture, the maximal excess (70%) of one of the 15-fluoro epimers was achieved. Possible mechanisms of dehydroxyfluorination of (+/-)-11-deoxyprostaglandin E1 esters with dialkylaminoflluorosulfurans were proposed. Methyl esters of 15-alpha-fluoro- and 15-beta-fluoro-11,15-dideoxyprostaglandin E1 exhibited moderate antiaggregation activity in rabbit platelet tests.

The effects of fluorodeoxy prostanoids on platelet aggregability were studied. It was shown that introduction of fluorine into positions 9, 11 or 15 of prostaglandin F2 alpha led to enhanced proaggregation activity. The most active compound among fluorodeoxy analogs was 15-fluoro derivative; bisfluoro analog was moderately active, and 11-fluoro compound had the least activity. In the group of fluorodeoxy prostaglandins E2, a contrary effect was registered. Thus, the most active compound was 1-fluoride and the least, 15-fluoride. The incorporation of fluorine into position 15 of prostacyclin led to insignificantly lower antiaggregatory activity just as this modification of 6-keto-prostaglandin F1 alpha was accompanied by a dramatic increase in its ability to inhibit platelet aggregation.

In a search for stable thromboxanomimetics the action of 11-fluoro-11-deoxyprostaglandin F2 alpha (11-fluoro-PGF2 alpha) on the aggregatory properties of platelets and the tone of the vascular, respiratory and gastrointestinal smooth muscles was studied. It was found that 11-fluoro-PGF2 alpha, in contrast to PGF2 alpha, induces platelet aggregation and exhibits a high activity with respect to smooth muscles sensitive to thromboxane A2 alpha (TXA2) and a low activity for smooth muscles sensitive to PGF2 alpha 9-11-epoxyimino-PGH2 (a specific antagonist of TXA2 receptors) competitively blocked the action of 11-fluoro-PGF2 alpha on vascular smooth muscles. Thus, 11-fluoro-PGF2 exhibits properties of a thromboxanomimetic that makes it possible to propose it for modelling TXA2-induced biological effects.

The effect of exchange of 15-hydroxyl for fluor on biological activity of PGF2 alpha and PGE2 on isolated smooth muscles of different organs has been studied. The exchange leads to significant increase in contractile (100-fold) and relaxation (1000-fold) activity of PGF2 alpha on smooth respiratory muscles. At the same time, the effect of 15-fluor-15-deoxyprostaglandin F2 alpha on smooth muscles of intestinal and vascular tracts did not differ from that of PGF2 alpha. Similar modification of PGE2 led to the decrease (10-fold) both in contractile and relaxation activity on all studied types of smooth muscles. The data obtained have been discussed within the boundaries of prostanoid receptor classification (Kennedy, 1982). Fluor derivative of PGF2 alpha may be used for pharmacological differentiation of EP-receptors.