[Study of osteoprotective and hypolipidemic effects of estrogen 8α-analogues].

The aim of this work was to study the ability of some estrogen 8α-analogues, that have CH3-group in the C-3 position, exhibit osteoprotective and cholesterolemic effects. The properties of these analogues was comparisoned with effects of native estradiol and 17α-ethynylestradiol (EE). We showed that compounds 3 ((d,l)-17ß-acethoxy-3-methoxy-8α-estra-1,3,5(10)-triene) and 4 ((d,l)-3-methoxy-8α-estra-1,3,5(10)-triene-17-one) had the same osteoprotective and cholesterolemic effects as EE. The utherotropic effects of compound 3 and EE were the same, while the utherotropic activity of 17-keto derivative (compound 4) was higher than effect of EE. The osteoprotective and cholesterolemic effects of compounds 5 and 6 (d- or l-17ß-acethoxy-3-methoxy-13-ethyl-8α-gone-1,3,5(10)-triene) were approximately the same, however the utherotropic action of these compounds was different: the compound 5 had significantly lower activity, but the compound 6 had the same effect in comparison with EE. Thus, all studied estrogen 8α-analogues may be used as basic constructions for structural modifications which is necessary as medications with while spectrum of biological properties.

[Synthesis, structure, and biological properties of some 8alpha-analogues of steroid estrogens with fluorine in position 2].

A total synthesis of 8alpha analogues of steroid estrogens with fluorine in position 2 was achieved. Structural features of these compounds were studied by the example of 17beta-acetoxy-2-fluoro-3-methoxy-8alpha-estra-1,3,5(10)-triene. It was shown that the 8alpha analogues of 2-fluorosubstituted steroid estrogens have a low uterotropic activity and retain the osteoprotective and hypocholesterolemic activities.

[An NMR study of the conformational mobility of 7alpha,8alpha analogues of steroid estrogens].

All the signals in the 1H and 13C NMR spectra of some analogues of 7alpha-methyl-8alpha- and 6-oxa-8alpha-steroid estrogens were completely assigned. Considering the values of nuclear Overhauser effect and vicinal coupling constants, these steroids were shown to exhibit a fast, on the NMR time scale, conformational equilibrium arising due to the inversion of ring B. The conformer populations were obtained from a comparison of the experimental and theoretical values of the dihedral angles and the interproton distances. This conformational equilibrium was shown to depend on the nature of atom in position 6: for the 7alpha-methyl-6-oxa-8alpha analogues of the steroid estrogens, the population of the conformer with the pseudoaxial orientation of the 7alpha-methyl group was observed to be decreased compared with the 7alpha-methyl-8alpha analogue.

[Synthesis and biological properties of 6-oxa-D-homo-8alpha analogues of steroid estrogens].

Modifications of 6-oxa-D-homo-8alpha-analogues of steroid estrogens were found to lead to a complete loss of the uterotropic and hypertriglyceridemic activities. These compounds may be promising for the design on their basis of inhibitors of the steroid hormone metabolism and transporters of other compounds to the estrogen target organs.

[Molecular model of binding of estradiol and 8-isoestradiol with estrogen alpha-receptor]. / Izuchenie sviazyvaniia éstradiola i 8-isoéstradiola s al'fa-retseptorom éstrogenov metodom moleculiarnogo modelirovaniia.

The complexes of the estrogen alpha-receptor with estradiol and 8-isoestradiol were comparatively analyzed. The computations of ligand-receptor complexes, carried out using the FLEXX program, allowed us to propose a model for the binding of the analogues of 8-isoestradiol. It was found that rings C and D of estradiol and 8-isoestradiol are similarly arranged in the ligand-binding pocket and coincide upon the superposition of the corresponding ligand-receptor complexes, whereas rings A and B do not coincide. The oxygen functions in position 17 of the estradiol analogues of both series coincide upon superposition, whereas the phenol 3-hydroxyl groups are 0.05 A apart. A comparison of the predicted biological properties of modified estradiol analogues of the natural and 8-isoseries with the available experimental data revealed their similarity. Synthetic 2-acetyl analogues of 8-isoestrogens were found to have no uterotropic activity, which is also consistent with the proposed model.

[Synthesis and study of B-nor-8-isoanalogs of steroid estrogens]. / Sintez i issledovanie B-nor-izoanalogov steroidnykh éstrogenov.

The study of the binding of estradiol B-nor-8-isonalogues to estrogen receptors from the rat uterus helped create the proposed model of the corresponding ligand-receptor complexes. The use of this model ensured the choice of such micromodifications in this steroid group that sharply decreased their hormonal activity. By the example of 16,16-dimethyl-D-homo-B-nor-8-isoestrone, we demonstrated the possibility of the synthesis of the estrogen analogues devoid of uterotropic activity but retaining immunosuppressive activity.

[NMR spectroscopy for studying structure and intramolecular dynamics of modified analogs of steroid hormones]. / Spektroskopiia IaMR v izuchenii prostranstvennoi struktury i vnutrimolekuliarnoi dinamiki modifitsirovannykh analogov steroidnykh gormonov.

Special features of the use of homo- and heteronuclear correlation methods of NMR in one and two dimensions for studying the spatial structure and intramolecular dynamics of modified analogues of steroid hormones (MASH) are considered. The application of these methods to the assignment of resonances in the high-field 1H NMR region and to the determination of the most stereospecifically important parameters, such as the vicinal constants of spin-spin coupling (3JH-H) and nuclear Overhauser effects (NOE), are discussed using the example of NMR studies of some estrogens and androgens at 300 MHz and on the basis of literature data. The most efficient combination of the methods and the necessary modification of each of them may be chosen considering the spectral and relaxation parameters of MASH in liquid medium, including the anisotropy of the overall diffusive motion. The characteristics of MASH are the wide use of correlations through long-range couplings (COSY-45 and DQF-COSY), the application of the 4,5JH-H constants for the determination of spatial structure, and the advantage of heteronuclear HSQC methods with and without 13C decoupling over the corresponding HMQC methods in both resolution and sensitivity. In the conformationally rigid MASH molecules, the anisotropy of the MASH diffusive motion in liquid adversely affects the determination of interproton distances by the calibrating processing method for the NOE difference and NOESY spectra: it results in both overestimated and underestimated distance values depending on the polar angle ratios of the reference and the determined distances. Under certain conditions, conformationally mobile MASH demonstrate the additional contribution of the scalar relaxation mechanism between the indirectly (scalarly) bound protons. This mechanism is responsible for the underestimated values of NOE and the corresponding errors in the distance determination.

[Study of analgesic effect of novel imidazoline derivatives and their effect on arterial pressure during pain]. / Izuchenie boleutoliaiushchego deistviia novykh proizvodnykh imidazolina i ikh vliianiia na arterial'noe davlenie v usloviiakh bolevogo vozdeistviia.

In rat experiments new imidazoline derivatives caused a pain-relieving effect and inhibited a rise in arterial pressure in pain. Fluoride derivatives of imidazoline in doses of 1, 2, and 4 mg/kg induced long-term analgesia, had no effect on the background arterial blood pressure (AP), and significantly reduced its nociceptive pressor responses. The bromide derivatives of imidazoline showed no noticeable pain-relieving activity but reduced the nociceptive AP shifts. The background AP parameters did not change in this case. The prospects of directed chemical modification of imidazoline derivatives to obtain new analgesics capable of reducing the undesirable hemodynamic manifestations of pain are discussed.

[Changes in the blood serum lipids and lipoproteins of rats in ovariectomy and to the administration of the methyl ester of 6-hydroxy-D-homo-8-isoestrone]. / Izmeneniia lipidov i lipoproteinov syvorotki krovi krys pri ovariéktomii i vvedenii metilovogo éfira 6-oksi-D-gomo-8-izoéstrona.

Ovariectomy of rats resulted in biphasic increase of the blood plasma cholesterol (on days 42-54, 70), the alteration of lipoprotein spectrum. The administration to ovariectomized rats of methyl ether 6-oxy-D-homo-8-isoestrone in a dose of 0.01 mg/kg brought about lowering of serum cholesterol and normalization of lipoproteins spectrum. The above trends were not observed after introduction of 0.01 mg/kg estradiol.

[Hypolipidemic action of the racemic methyl ester of 16,16-dimethyl-D-homo-8-isoestrone]. / Gipolipidemicheskoe deistvie ratsemicheskogo metilovogo éfira 16,16-dimetil-D-gomo-8-izoéstrona.

Racemic 16,16-dimethyl-D-homo-8-isoestrone methyl ester (substance 1) was shown to decrease the content of cholesterol in blood serum and liver tissue of animals with induced hyperlipidemia (rats, guinea pigs, rabbits) as well as to decrease the rate of atherosclerotic impairments in rabbit aorta. As distinct from usual estrogen, the substance I did not cause hypertriglyceridemia but normalized triglycerides in blood and liver tissue. Substance I exhibited low toxic effects.

[Pharmacological activity of modified analogs of steroid estrogens. Racemic 8-isoestradiol]. / Izuchenie farmakologicheskoi aktivnosti modifitsirovannykh analogov steroidnykh éstrogenov. Ratsemicheskii 8-izoéstradiol.

The authors have studied pharmacological activity of an estradiol isoanalog-8-isoestradiol. The drug has been shown to possess dissociated hormonal properties. Having a relatively high vaginotropic and antifertile activity, the drug exerts a negligible antigonadotropic effect on the pituitary and a fairly weak uterotropic action.