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1.
Steroids ; 145: 5-18, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30753845

RESUMO

Progesterone (P4) and its analogues regulate various reproductive processes, such as ovulation, implantation, pregnancy maintenance and delivery. In these processes, an important role is played by the immune cells recruited to the female reproductive organs and tissues, where they are exposed to the action of P4. Progestins regulate cellular processes, acting through nuclear steroid receptors (nSRs), membrane P4 receptors (mPRs), and through the sensors. It remains unclear, what type of receptors is used by P4 and its derivatives to exert their effect on the immune cells and how similar their effects are in different types of these cells. We have previously synthesized new progesterone derivatives, among which two selective mPRs ligands, not interacting with nSRs were identified. The objective of this study was to examine the effects of P4 and new selective mPRs ligands on the expression of pro- and anti-inflammatory cytokines in activated human peripheral blood mononuclear cells (PBMCs), THP-1 monocyte cells, and Jurkat T cells. It was demonstrated that the action of P4 and selective ligands was unidirectional, but in different types of the immune cells, their effects were different, and sometimes even opposite. In PBMCs, exposure to these steroids resulted in the increase of mRNA and secreted protein levels of IL-1ß, TNFα, and IL-6 cytokines, as well as in the increase of INFγ mRNA level, decrease of IL-2 mRNA level, increase of TGFß mRNA level, and decrease of IL-4 mRNA and IL-10 secreted protein levels. In monocytes, similarly to PBMCs, expression of IL-1ß and TNFα mRNA was increased, but expression of IL-10 was also increased, and the TGFß expression statistically significantly remained the same. In Jurkat T cells, expression of IL-2 and TNFα mRNA decreased, while expression of IL-10 increased, and expression of TGFß did not change. Thus, progestins act on the immune cells through mPRs and have both pro- and anti-inflammatory effects, depending on the phenotypes of these cells. The data obtained are important for understanding the complexity of the immune system regulation by progestins, which depends on the type of the immune cells and individual characteristics of the immune system.


Assuntos
Membrana Celular/metabolismo , Fatores Imunológicos/farmacologia , Progesterona/farmacologia , Receptores de Progesterona/metabolismo , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Células Jurkat , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Ligantes , Masculino , RNA Mensageiro/genética , Caracteres Sexuais , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
2.
Biochemistry (Mosc) ; 83(5): 574-585, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29738691

RESUMO

Identification of progesterone selective agonists and antagonists that act through one of the nuclear progesterone receptor isoforms is of particular importance for the development of tissue-specific drugs in gynecology and anticancer therapy. Fourteen pregna-D'6- and pregna-D'3-pentarane progesterone derivatives with 16α,17α-cycloalkane groups and two progesterone 3-deoxyderivatives were examined for their ability to regulate transcriptional activity of human nuclear progesterone receptor isoform B (nPR-B) expressed in Saccharomyces cerevisiae yeast. Transcriptional activity of nPR-B was measured from the expression of the ß-galactosidase reporter gene with a hormone-responsible element in the promoter. Among the compounds tested, two were full progesterone agonists, four were partial agonists, one compound possessed both agonistic and antagonistic activity, one compound displayed only partial antagonistic activity, and eight compounds did not show any activity. Modifications of the pentarane structure, precisely, introduction of an additional double bound in the A or B rings and/or modification at the 6th position of progesterone, lead to a switch from the complete agonistic activity to partial agonistic or mixed activities. These modifications enable progestins to act as selective modulators of progesterone receptor. Steroids with reduced A-ring and 3-ketogroups lose their ability to regulate PR-B activity. Both 3-deoxycompounds, being selective ligands of progesterone membrane receptors, do not affect PR-B activity.


Assuntos
Núcleo Celular/efeitos dos fármacos , Progesterona/farmacologia , Receptores de Progesterona/agonistas , Receptores de Progesterona/antagonistas & inibidores , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/genética , Transcrição Gênica/efeitos dos fármacos , Ativação Transcricional/efeitos dos fármacos , Núcleo Celular/metabolismo , Modelos Biológicos , Progesterona/análogos & derivados , Progesterona/química , Receptores de Progesterona/genética , Saccharomyces cerevisiae/citologia , Saccharomyces cerevisiae/metabolismo , Transcrição Gênica/genética , Ativação Transcricional/genética
3.
Biochemistry (Mosc) ; 82(2): 140-148, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28320297

RESUMO

The search of selective agonists and antagonists of membrane progesterone receptors (mPRs) is a starting point for the study of progesterone signal transduction mechanisms mediated by mPRs, distinct from nuclear receptors. According to preliminary data, the ligand affinity for mPRs differs significantly from that for classical nuclear progesterone receptors (nPRs), which might indicate structural differences in the ligand-binding pocket of these proteins. In the present work, we analyzed the affinity of several progesterone derivatives for mPRs of human pancreatic adenocarcinoma BxPC3 cell line that is characterized by a high level of mPR mRNA expression and by the absence of expression of nPR mRNA. The values were compared with the affinity of these compounds for nPRs. All tested compounds showed almost no affinity for nPRs, whereas their selectivity towards mPRs was different. Derivatives with an additional 19-hydroxyl group and removed 3-keto group had the highest selectivity for mPRs. These results suggest these compounds as the most selective progesterone analogs for studying the mechanisms of progestin action via mPRs.


Assuntos
Membrana Celular , Progesterona , Receptores de Progesterona , Linhagem Celular Tumoral , Membrana Celular/química , Membrana Celular/metabolismo , Humanos , Progesterona/análogos & derivados , Progesterona/síntese química , Progesterona/química , Progesterona/farmacocinética , Receptores de Progesterona/biossíntese , Receptores de Progesterona/química
4.
Biomed Khim ; 62(3): 290-4, 2016 Mar.
Artigo em Russo | MEDLINE | ID: mdl-27420621

RESUMO

The cytotoxic activity of synthetic progestins (pregna-D'-pentaranes) II-V full agonists of the progesterone receptor (PR) for PR-positive and PR-negative cells of human breast carcinoma was studied. These compounds were more active in the PR-positive MCF-7 cells than in the PR-negative MDA-MB-453 cells. Cytotoxic effects of tested compounds against normal epithelial MDCK cells were not found. Molecular modeling of studied steroids with PR showed that all progestins with close energy values can bind to the ligand binding domain (LBD) of PR and the magnitude of the energy exceeds the value estimated for the progesterone molecule. Thus, the studied progestins are active against different molecular subtypes of breast cancer and represent a promising class of chemical compounds for oncology.


Assuntos
Progestinas/farmacologia , Receptores de Progesterona/antagonistas & inibidores , Animais , Cães , Humanos , Células MCF-7 , Células Madin Darby de Rim Canino , Simulação de Acoplamento Molecular , Progestinas/química , Progestinas/toxicidade , Ligação Proteica , Receptores de Progesterona/metabolismo
5.
Eksp Klin Farmakol ; 79(9): 22-24, 2016.
Artigo em Russo | MEDLINE | ID: mdl-29787667

RESUMO

We have studied the effect of new ligands of progesterone receptors, including pregna-D'-pentaran 6-methoxyimino-16a,17a-cyclohexanopregn-4-en-3,20-dio-ne (K1047), 17a-acetoxy-3b-butanoyloxy-6-methylpregna-4,6-dien-20-one (buterol), progesterone (P4), and medroxyprogesterone acetate on the viability of HeLa cells and expression of estrogen receptor-alpha (Era) mRNA gene in these cells. K1I047 and buterol exhibited high cytostatic activity, which exceeded the activity of reference compounds on the average by 15% (p < 0.05). Both buterol and K-1047 (at 10(-6)M) effectively suppressed ERa mRNA gene expression in HeLa cell culture by 83.4 - 9 8.6%.


Assuntos
Receptor alfa de Estrogênio/biossíntese , Regulação da Expressão Gênica/efeitos dos fármacos , Progesterona , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Progesterona/análogos & derivados , Progesterona/farmacologia
6.
Biochemistry (Mosc) ; 78(10): 1134-6, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24237147

RESUMO

The interactions between E- and Z-isomers of 3-O-methoxyimino-pregn-4-ene-20-one and its 17α-hydroxy derivative and transcortin from human blood were investigated. The substitution of the progesterone 3-oxo group for a 3-O-methoxyimino group was shown to diminish the affinity of the steroid for transcortin by approximately one order of magnitude irrespective of the substituent's orientation. The data suggests that progesterone derivatives substituted thereby must have higher bioavailability compared to progesterone and must not significantly affect the biodynamics of glucocorticoid in vivo.


Assuntos
Sangue/metabolismo , Iminas/farmacologia , Pregnenolona/análogos & derivados , Progestinas/metabolismo , Transcortina/metabolismo , Relação Dose-Resposta a Droga , Humanos , Iminas/sangue , Iminas/química , Estrutura Molecular , Pregnenolona/sangue , Pregnenolona/química , Pregnenolona/farmacologia , Progestinas/química , Ligação Proteica/efeitos dos fármacos , Relação Estrutura-Atividade , Transcortina/química
7.
Biochemistry (Mosc) ; 78(3): 236-43, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23586716

RESUMO

A number of progesterone derivatives were assayed in terms of their affinity for recombinant human membrane progesterone receptor alpha (mPRα) in comparison with nuclear progesterone receptor (nPR). The 16α,17α-cycloalkane group diminished an affinity of steroids for mPRα without significant influence on affinity for nPR, thus rendering a prominent selectivity of ligands for nPR. On the contrary, substitution of methyl at C10 for ethyl or methoxy group moderately increased the affinity for mPRα and significantly lowered the affinity for nPR. A similar but even more prominent effect was observed upon substitution of the 3-oxo group for the 3-O-methoxyimino group. A significant preference towards mPRα was also rendered by the 17α-hydroxy group and additional C6-C7-double bond. The data suggest that the modes of ligand interaction with mPRα and nPR in the C3 region of the steroid molecule are different. One can speculate that combination of the above substitutions at C17, C10, C6, and C3 may give ligand(s) with high specificity towards mPRα over nPR.


Assuntos
Progesterona/análogos & derivados , Receptores Acoplados a Proteínas G/agonistas , Receptores de Progesterona/agonistas , Desenho de Fármacos , Humanos , Cinética , Ligantes , Estrutura Molecular , Progesterona/química , Progesterona/metabolismo , Ligação Proteica , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Progesterona/química , Receptores de Progesterona/metabolismo
8.
Biomed Khim ; 59(6): 622-35, 2013.
Artigo em Russo | MEDLINE | ID: mdl-24511674

RESUMO

A series of 42 steroid ligands was used to predict a binding affinity to progesterone receptor. The molecules were the derivatives of 16alpha,17alpha-cycloalkanoprogesterones. Different methods of prediction were used and analyzed such as CoMFA and artificial neural networks. The best result (Q2 = 0.91) was obtained for a combination of molecular docking, molecular dynamics simulation and artificial neural networks. A predictive power of the model was validated by a group of 8 pentarans synthesized separately and tested in vitro (R2test = 0.77). This model can be used to determine the affinity level of the ligand to progesterone receptor and accurate ranking of binding compounds.


Assuntos
Simulação de Acoplamento Molecular/métodos , Progesterona/análogos & derivados , Progesterona/química , Receptores de Progesterona/agonistas , Animais , Humanos , Ligantes , Simulação de Acoplamento Molecular/estatística & dados numéricos , Estrutura Molecular , Relação Quantitativa Estrutura-Atividade
9.
Bioorg Khim ; 36(2): 283-8, 2010.
Artigo em Russo | MEDLINE | ID: mdl-20531488

RESUMO

1,2-Tritium-labeled 3-(O-carboxypropyl)- and 3-(O-carbomethoxypropyl)-oximes of 6alpha-methyl-16alpha,17alpha-cyclohexanopregn-4-ene-3,20-diones were obtained by the homogeneous catalytic hydrogenation of 1,2-dehydroprecursors with gaseous tritium and the subsequent separation of the resulting mixtures by HPLC. The specific radioactivities of 50-55 Ci/mmol were prepared using tris-(triphenylphosphine)-rhodium chloride.


Assuntos
Oximas/síntese química , Pregnenodionas/síntese química , Catálise , Marcação por Isótopo , Compostos Organometálicos , Compostos Organofosforados , Oximas/química , Pregnenodionas/química , Trítio
10.
Bioorg Khim ; 33(3): 332-6, 2007.
Artigo em Russo | MEDLINE | ID: mdl-17682389

RESUMO

(19R)- and (19S)-tert-Butyldimethylsilyl (TBS) ethers of 19-hydroxy-19-vinyl-16alpha,17alpha-cyclohexanopregn-5-en-20-ones were synthesized. These compounds containing the 1,5-oxydienoic motif were subjected to the anionic oxy-Cope rearrangement to obtain 3beta-TBS ether of 6beta-(3-oxopropyl)-16alpha,17alpha-cyclohexano-19-nor-pregn-5(10)-en-20-one. The structures of the compounds synthesized were confirmed by the analysis of their H and 13C NMR spectra.


Assuntos
Pregnanos/síntese química , Pregnenos/química , Espectroscopia de Ressonância Magnética , Pregnanos/química , Pregnenos/síntese química , Estereoisomerismo
11.
Bioorg Khim ; 31(3): 227-38, 2005.
Artigo em Russo | MEDLINE | ID: mdl-16004380

RESUMO

The manner in which multifunctional steroid hormones realize their separate biological functions in mammal organisms is considered. This study is carried out on the basis of a systematic set of progesterone analogues, which we developed and described in part I of the review. This set has for the first time enabled the use of compounds of this type for studying the pathways and realization mechanisms of separate biological functions of steroid hormones. The interaction of pregna-D'-pentaranes with the classical progesterone receptor, their independent influence on the myometrium and ovogenesis, and some nonclassical effects are described. A scheme of realization is suggested for the biological functions already known, newly discovered, and presumed by us that, during pregnancy, are fulfilled in mammal organisms by progesterone and its nearest metabolite, dihydroprogesterone. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2005, vol. 31, no. 3; see also http://www.maik.ru.


Assuntos
20-alfa-Di-Hidroprogesterona/metabolismo , Miométrio/fisiologia , Oogênese/fisiologia , Gravidez/metabolismo , Progestinas/antagonistas & inibidores , Progestinas/metabolismo , Animais , Feminino , Humanos , Prenhez
12.
Bioorg Khim ; 31(2): 115-29, 2005.
Artigo em Russo | MEDLINE | ID: mdl-15889785

RESUMO

The synthesis, modification, structure, and biological activity in vivo of the 16alpha,17alpha-cycloalkanoprogesterone (pregna-D'-pentarane) analogues of progesterone are described. A possibility of separation of their biological functions has been demonstrated. A systematic synthesis of a set of uniform compounds that differ in a limited number of alterable parameters was developed. It resulted in an instrument useful for the investigation of pathways and mechanisms by which the steroid hormones fulfill their biological functions and for the probable discovery of new functions masked by the wide effects of native compounds.


Assuntos
Hormônios Esteroides Gonadais/fisiologia , Progesterona/análogos & derivados , Progesterona/farmacologia , Progestinas/antagonistas & inibidores , Progestinas/farmacologia , Animais , Feminino , Masculino , Progesterona/síntese química , Relação Estrutura-Atividade
13.
Probl Endokrinol (Mosk) ; 51(5): 47-49, 2005 Oct 15.
Artigo em Russo | MEDLINE | ID: mdl-31627599

RESUMO

The effects of 16α, 17α -cyclohexanodihydroprogesterone, the structural analogues of the closest progesterone metabolites (4,5-dihy-droprogesterones) on the uterine tissues of intact, impregnated, and pseudopregnant rats has demonstrated that they cause uterine epithelial destruction. This effect does not affect the rate and completeness of fetal implantation, but it may play a role during labor, by facilitating fetal rejection. Earlier studies have indicated that the above analogues of the metabolites of progesterone eliminate the latter-induced oxytocin receptor blockade and cause myometrial destruction in pseudopregnant animals. These facts suggest that by accumulating by the end of pregnancy, the natural progesterone metabolites (4.5-dihydroprogesterones) can act as trigger compounds - "labor hormones".

14.
Bioorg Khim ; 30(3): 301-7, 2004.
Artigo em Russo | MEDLINE | ID: mdl-15344660

RESUMO

Competition of a number of progesterone 16alpha,17alpha-cycloalkane derivatives with 3H-labeled ligands for the binding sites of the rat uterine progesterone receptor, uterine pentaranophilin, and blood serum pentaranophilin was studied. We found that the selective ligands for the progesterone receptor are progesterone, 16alpha,17alpha-cyclopropanoprogesterone, and 16alpha,17alpha-cyclopent-3'-enoprogesterone and the selective ligands for serum pentaranophilin are 6alpha-methyl-16alpha,17alpha-cyclohexanopregna-1,4-diene-3,20-dione and 3beta-hydroxy-16alpha,17alpha-cyclohexanopregn-5-en-20-one. No selective ligands for the uterine pentaranophilin were found. The majority of substituents in rings A, B, and D' we studied decreased the affinity of ligands for all the three proteins. The substitution of the delta5-3beta-hydroxy grouping for the delta4-3-keto grouping exerted the strongest negative effect in the case of the progesterone receptor and the uterine pentaranophilin, whereas the introduction of the 3',4'-dimethyl grouping strongly inhibited the ligand affinity for the uterine pentaranophilin. The extent and even the direction of the effect of a substituent on the affinity of ligands for the proteins substantially depended on the presence of other substituents in the steroid molecules. We hypothesized that a certain similarity exists between three proteins studied in respect to the structures of their ligand-binding pockets. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2004, vol. 30, no. 3; see also http://www.maik.ru.


Assuntos
Cicloparafinas/química , Progesterona/análogos & derivados , Proteínas/metabolismo , Receptores de Progesterona/metabolismo , Animais , Ligação Competitiva , Proteínas Sanguíneas/metabolismo , Feminino , Ligantes , Progesterona/química , Ratos , Receptores de Progesterona/fisiologia , Útero/metabolismo
15.
Steroids ; 68(4): 351-9, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12787896

RESUMO

Steroid ligands are known to affect the interactions of their respective receptors with DNA. In the present study, the possibility of DNA interference in progesterone receptor-ligand interactions was investigated. An oligonucleotide containing a hormone response element (HRE) was shown to decrease the dissociation rate of complexes of [3H]progesterone or [3H]16alpha,17alpha-cycloalkanoprogesterones with PRs from rabbit and rat uterine cytosol. The extent to which the oligonucleotide affected the dissociation constant varied from about 4- to 1.5-fold depending on the ligand structure and was ranked in the following order: progesterone>16alpha,17alpha-cyclopropanoprogesterone approximately 16alpha,17alpha-cyclopentanoprogesterone>/=16alpha,17alpha-cyclohex-2'-enoprogesterone approximately 6alpha-methyl-16alpha,17alpha-cyclohexanoprogesterone>/=16alpha,17alpha-cyclohexanoprogesterone. The control oligonucleotide lacking HRE had a weak effect, if any, on the dissociation kinetics. No influence of the HRE-containing oligonucleotide on the equilibrium binding of ligands to PR was observed. The results suggest that the DNA partner affects binding of PR to its ligand.


Assuntos
DNA/farmacologia , Progesterona/química , Receptores de Progesterona/química , Animais , Sequência de Bases , Citosol/química , Citosol/metabolismo , Feminino , Cinética , Ligantes , Oligonucleotídeos/genética , Oligonucleotídeos/farmacologia , Progesterona/análogos & derivados , Progesterona/metabolismo , Progestinas/química , Progestinas/metabolismo , Coelhos , Ensaio Radioligante , Ratos , Receptores de Progesterona/metabolismo , Elementos de Resposta/genética , Trítio , Útero/metabolismo
16.
Bull Exp Biol Med ; 136(5): 460-3, 2003 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-14968160

RESUMO

The combined cytostatic effect of doxorubicin and gestagens progesterone, medroxyprogesterone acetate, mecigestone, and butagest on doxorubicin-resistant and doxorubicin-sensitive human breast cancer MCF-7 cells was studied by the MTT assay. On the 6th day of incubation progesterone, medroxyprogesterone acetate, mecigestone, and butagest in high concentrations (10(-5) M) potentiated the cytostatic action of doxorubicin in sensitive and resistant cells by 30-50%. Potentiation of the cytostatic effect produced by doxorubicin in sensitive cells is related to intrinsic cytotoxic activity of gestagens. In resistant cells these changes are associated with potentiation of the effect of doxorubicin.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias da Mama/tratamento farmacológico , Doxorrubicina/administração & dosagem , Progestinas/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Progestinas/química
17.
Bioorg Khim ; 28(3): 261-8, 2002.
Artigo em Russo | MEDLINE | ID: mdl-12077853

RESUMO

Changes in the uterus morphology of mature female rats were studied on the model of pseudopregnancy after treatment with the progestin 16 alpha,17 alpha-cyclohexanoprogesterone (PR) and the antirpogestins 5 alpha(H)-16 alpha,17 alpha-cyclohexano-4,5-dihydroprogesterone (APR1) and 5 beta(H)-16 alpha,17 alpha-cyclohexano-4,5-dihydroprogesterone (APR2). The rats were preliminarily estrogenized with 17 beta-estradiol at a dose of 1 microgram/(animal day) for 4 days and then treated with PR at a dose of 0.2 mg/(animal day) for 14 days. The first group was then left without any treatment, whereas APR1 and APR2 were injected at the dose of 0.2 mg/(animal day) for 4 days to the animals of the second and the third groups, respectively. Light and electron microscopy of the uterus preparations demonstrated that the PR action provoked a complete pseudopregnancy picture characterized by the endometrium functionalization and the myometrium hypertrophy. Subsequent treatment with APR1 and APR2 caused the hypertrophy to cease, which had a more pronounced effect in the case of APR1. At the same time, some indications of the endometrium functionalization remained observable after treatment with APR1 and APR2. The specific binding sites for 3H-labeled APR1 and APR2 were absent from the uterus cytosol for the rats gestagenized with PR.


Assuntos
Cicloexanos/farmacologia , Progesterona/análogos & derivados , Progesterona/farmacologia , Útero/efeitos dos fármacos , Animais , Sítios de Ligação , Cicloexanos/química , Estradiol/farmacologia , Feminino , Técnicas In Vitro , Progesterona/química , Pseudogravidez , Ratos , Estereoisomerismo , Útero/metabolismo , Útero/ultraestrutura
18.
Bioorg Khim ; 28(3): 258-60, 2002.
Artigo em Russo | MEDLINE | ID: mdl-12077852

RESUMO

6-O-(3-Methoxycarbonylpropyl)- and 6-O-(3-carboxypropyl)oximes of 16 alpha,17 alpha-cyclohexanopregn-4-ene-3,6,20-trione labeled by tritium in position 1,2 were synthesized. When using homogenous catalysts, the molar radioactivity of the resulting preparations was 1.5-1.7 PBq/mol.


Assuntos
Cicloexanos/síntese química , Oximas/síntese química , Pregnenos/síntese química , Catálise , Cicloexanos/química , Marcação por Isótopo , Espectroscopia de Ressonância Magnética , Oximas/química , Pregnenos/química , Trítio
19.
Bioorg Khim ; 28(3): 251-7, 2002.
Artigo em Russo | MEDLINE | ID: mdl-12077851

RESUMO

The binding of [3H]progesterone and [3H] 16 alpha,17 alpha-cycloalkanoprogesterones to proteins from rat, rabbit, and human uteri and other organs was studied. We found that 16 alpha,17 alpha-cycloalkanoprogesterone derivatives display affinities for the uterine progesterone receptors comparable with that of the natural hormone and no substantial species differences in the affinity. Rabbit uterus was found to have no proteins distinct from the progesterone receptor that specifically bind [3H] 16 alpha,17 alpha-cycloalkanoprogesterones. At the same time, in the human uterus, we found another protein that binds some of these progesterone derivatives; it turned out to be similar to the protein from rat uterus. A similar protein with the same selectivity and affinity for steroids was also found in rat and human kidneys. Blood serum, liver, lung, and a number of other tissues were found to contain a protein of the third type that binds the same 16 alpha,17 alpha-cycloalkanoprogesterones and exhibits submicromolar Kd values for these steroids and a very low affinity for progesterone. We speculated that the introduction of a bulky substituent adjacently to the 17 beta-side chain of progesterone could result in a change in the general biodynamics of the derivative including its transport, uptake, and accumulation in tissues, which may determine the selectivity of its effect.


Assuntos
Cicloparafinas/metabolismo , Progesterona/análogos & derivados , Progesterona/metabolismo , Receptores de Progesterona/metabolismo , Animais , Ligação Competitiva , Humanos , Ligantes , Especificidade de Órgãos , Progesterona/química , Coelhos , Ensaio Radioligante , Ratos , Especificidade da Espécie , Relação Estrutura-Atividade
20.
Steroids ; 67(5): 323-32, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11958787

RESUMO

Electrophoretic mobility shift assay was used to determine whether pregna-D'-pentaranes allow progesterone receptor (PR) from rat uterine cytosol to bind hormone response element (HRE)-containing oligonucleotide duplexes and to measure the affinity of this interaction. The formation of DNA-protein complexes in low salt medium was progesterone-related ligand-, temperature-, and PR-dependent, and specific for HRE. The highest affinity of PR to DNA (equilibrium K(a) = 0.420 +/- 0.185 nM(-1)) was found in the presence of the partial agonist/antagonist RU486, while the lowest affinity (K(a) = 0.074 +/- 0.013 nM(-1)) was demonstrated with the full agonist 6alpha-methyl-16alpha,17alpha-cyclohexanoprogesterone. With the exception of the strong full agonist R5020, there was a tendency toward correlation between the induced lower affinity of PR for DNA in the context of tyrosine aminotransferase HRE and the full agonistic activity of tested compounds.


Assuntos
DNA/metabolismo , Progesterona/química , Receptores de Progesterona/metabolismo , Animais , Sítios de Ligação , Citosol , Primers do DNA/química , Ensaio de Desvio de Mobilidade Eletroforética , Feminino , Cinética , Estrutura Molecular , Progesterona/análogos & derivados , Progesterona/metabolismo , Regiões Promotoras Genéticas , Ratos , Ratos Wistar , Elementos de Resposta , Ativação Transcricional , Tirosina Transaminase/genética , Tirosina Transaminase/metabolismo , Útero/metabolismo
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