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1.
Eur J Pharmacol ; 881: 173187, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32446713

RESUMO

Neuroactive steroid 20-oxo-5ß-pregnan-3α-yl L-glutamyl 1-ester (PA-Glu), a synthetic analogue of naturally occurring 20-oxo-5ß-pregnan-3α-yl sulfate (pregnanolone sulfate, PA-S), inhibits N-methyl-D-aspartate (NMDA) receptors and possesses neuroprotective properties and minimal adverse effects. Herein, we report in vivo effects of new structural modifications of the PA-S molecule: a nonpolar modification of the steroid D-ring (5ß-androstan-3α-yl L-glutamyl 1-ester, AND-Glu), attachment of a positively charged group to C3 (20-oxo-5ß-pregnan-3α-yl L-argininate dihydrochloride salt, PA-Arg) and their combination (5ß-androstan-3α-yl L-argininate dihydrochloride salt, AND-Arg). The first aim of this study was to determine the structure-activity relationship for neuroprotective effects in a model of excitotoxic hippocampal damage in rats, based on its behavioral correlate in Carousel maze. The second aim was to explore side effects of neuroprotective steroids on motor functions, anxiety (elevated plus maze) and locomotor activity (open field) and the effect of their high doses in mice. The neuroprotective properties of PA-Glu and AND-Glu were proven, with the effect of the latter appearing to be more pronounced. In contrast, neuroprotective efficacy failed when positively charged molecules (PA-Arg, AND-Arg) were used. AND-Glu and PA-Glu at the neuroprotective dose (1 mg/kg) did not unfavorably influence motor functions of intact mice. Moreover, anxiolytic effects of AND-Glu and PA-Glu were ascertained. These findings corroborate the value of research of steroidal inhibitors of NMDA receptors as potential neuroprotectants with slight anxiolytic effect and devoid of behavioral adverse effects. Taken together, the results suggest the benefit of the nonpolar D-ring modification, but not of the attachment of a positively charged group to C3.


Assuntos
Comportamento Animal/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Pregnanolona/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sulfatos/farmacologia , Animais , Relação Dose-Resposta a Droga , Agonistas de Aminoácidos Excitatórios/toxicidade , Antagonistas de Aminoácidos Excitatórios/síntese química , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/fisiopatologia , Locomoção/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , N-Metilaspartato/toxicidade , Fármacos Neuroprotetores/síntese química , Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Ratos Long-Evans , Receptores de N-Metil-D-Aspartato/metabolismo , Relação Estrutura-Atividade , Sulfatos/síntese química
2.
Org Lett ; 20(4): 946-949, 2018 02 16.
Artigo em Inglês | MEDLINE | ID: mdl-29364682

RESUMO

A unique asymmetric total synthesis of the unnatural enantiomer of pregnanolone, as well as a study of its biological activity at the NMDA receptor, is reported. The asymmetry is introduced by a highly atom-economic organocatalytic Robinson annulation. A new method for the construction of the cyclopentane D-ring consisting of CuI-catalyzed conjugate addition and oxygenation followed by thermal cyclization employing the persistent radical effect was developed. ent-Pregnanolone sulfate is surprisingly only 2.6-fold less active than the natural neurosteroid.


Assuntos
Pregnanolona/síntese química , Ciclização , Estrutura Molecular , Receptores de N-Metil-D-Aspartato , Estereoisomerismo , Sulfatos
3.
J Med Chem ; 56(6): 2323-36, 2013 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-23421641

RESUMO

(25R)-3ß-Hydroxy-5α-spirostan-12-one (hecogenin) and 11α-hydroxypregn-4-ene-3,20-dione (11α-hydroxyprogesterone) were used as starting materials for the synthesis of a series of 11- and 12-substituted derivatives of 5ξ-pregnanolone (3α-hydroxy-5α-pregnan-20-one and 3α-hydroxy-5ß-pregnan-20-one), the principal neurosteroid acting via γ-aminobutyric acid (GABA). These analogues were designed to study the structural requirements of the corresponding GABAA receptor. Their biological activity was measured by in vitro test with [(3)H]flunitrazepam as radioligand in which allopregnanolone and its active analogues stimulated the binding to the GABAA receptor. Analysis of the SAR data suggests dependence of the flunitrazepam binding activity on the hydrophobic-hydrophilic balance of the groups at the C-ring edge rather than on specific interactions between them and the receptor.


Assuntos
Pregnanolona/síntese química , Pregnanolona/metabolismo , Relação Quantitativa Estrutura-Atividade , Receptores de GABA-A/metabolismo , Animais , Técnicas de Química Sintética , Camundongos , Modelos Moleculares , Neurônios/metabolismo , Pregnanolona/análogos & derivados , Conformação Proteica , Receptores de GABA-A/química
4.
Steroids ; 77(3): 282-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22209708

RESUMO

20-Oxo-5ß-[9,12,12-(2)H(3)]pregnan-3α-yl-l-glutamyl 1-ester 11 was synthesized as an internal standard for quantification of a neuroprotective NMDA receptor ligand, 20-oxo-5ß-pregnan-3α-yl-l-glutamyl 1-ester 18 and its metabolites, in plasma and tissue. 11α-Hydroxy-progesterone (1) was reduced under basic conditions to yield the corresponding 5ß-steroid. Protection of the 3- and 20-oxo groups and oxidation of the 11α-hydroxy group was then followed by a deuterium exchange, conducted under basic conditions using deuterated methanol. Next, the carbonyl moiety at C-11 was reduced and the 11α-hydroxyl group removed through utilization of the Barton-McCombie reaction. Subsequent deprotection of the 3- and 20-acetals and stereoselective reduction of the 3-oxo group gave the desired trideuterated pregnanolone (8). This was coupled with protected glutamic acid, which was then deprotected to yield [9,12,12-(2)H(3)]-pregnanolone glutamate (11) with >99% isotopic purity.


Assuntos
Deutério/química , Glutamatos/química , Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Cromatografia em Camada Fina , Hidroxiprogesteronas/química , Marcação por Isótopo/métodos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Oxirredução , Pregnanolona/química , Solventes/química
5.
Bioorg Med Chem ; 17(18): 6526-33, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19709888

RESUMO

The synthesis of new analogues of allopregnanolone with a bridged sulfamidate ring over the beta-face of ring A has been achieved from easily available precursors, using an intramolecular aziridination strategy. The methodology also allows the synthesis of 3alpha-substituted analogues such as the 3alpha-fluoro derivative. GABA(A) receptor activity of the synthetic analogues was evaluated by assaying their effect on the binding of [(3)H]flunitrazepam and [(3)H]muscimol. The 3alpha-hydroxy-2,19-sulfamoyl analogue and its N-benzyl derivative were more active than allopregnanolone for stimulating binding of [(3)H]flunitrazepam. For the binding of [(3)H]muscimol, both synthetic analogues and allopregnanolone stimulated binding to a similar extent, with the N-benzyl derivative exhibiting a higher EC(50). The 3alpha-fluoro derivative was inactive in both assays.


Assuntos
Pregnanolona/análogos & derivados , Pregnanolona/farmacologia , Receptores de GABA-A/metabolismo , Animais , Membrana Celular/metabolismo , Cerebelo/metabolismo , Masculino , Modelos Moleculares , Pregnanolona/síntese química , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade , Sulfonamidas/química
6.
J Med Chem ; 52(7): 2119-25, 2009 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-19290593

RESUMO

The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by previously prepared allopregnanolone with a 16alpha-bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16alpha with the goal of increasing water solubility, brain accessibility, and potency of neuroactive steroids. The Michael addition to derivatives of pregn-16-en-20-one was the key reaction step. The link between the steroid skeleton and the new side chain was either a methylene group (when diethyl malonate was added) or an oxygen atom (when a hydroxy derivative was added). [(35)S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABA(A) receptors. Although none of them was more potent than the above ammonium salt, which stimulated this study, their nonionic nature should not prevent their passage into the brain.


Assuntos
Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Animais , Encéfalo/metabolismo , Moduladores GABAérgicos/síntese química , Moduladores GABAérgicos/farmacologia , Técnicas In Vitro , Masculino , Pregnanolona/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade
7.
Drug Dev Ind Pharm ; 33(6): 677-82, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17613031

RESUMO

Directly compressed sustained release pellets were prepared from material consisting of a molecule of 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) covalently linked via carbonate moieties to two molecules of 5-flourouracil (5FU) to form a novel THS-BIS-5FU codrug for the treatment of angiogenesis. Dissolution and drug release was tested in vitro in 0.1M phosphate buffer (pH 7.4), human serum, and vitreous humor. The results suggest that neat THS-BIS-5FU codrug pellets are useful for sustained release ocular delivery of the parent compounds, and that the unique physicochemical properties of the codrug allow slow dissolution and rapid release of the two parent drugs. This codrug formulation is regarded as a "chemical delivery" system that involves dissolution of the codrug as the rate-limiting step followed by rapid hydrolysis of the carbonate ester linkages to release the parent drugs via sustained delivery.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Fluoruracila/análogos & derivados , Fluoruracila/administração & dosagem , Pregnanos/administração & dosagem , Pregnanolona/análogos & derivados , Pró-Fármacos/administração & dosagem , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/farmacocinética , Animais , Disponibilidade Biológica , Bovinos , Cromatografia Líquida de Alta Pressão , Preparações de Ação Retardada , Sistemas de Liberação de Medicamentos , Fluoruracila/síntese química , Fluoruracila/química , Fluoruracila/farmacocinética , Humanos , Técnicas In Vitro , Estrutura Molecular , Pregnanos/síntese química , Pregnanos/farmacocinética , Pregnanolona/administração & dosagem , Pregnanolona/síntese química , Pregnanolona/química , Pregnanolona/farmacocinética , Pró-Fármacos/síntese química , Pró-Fármacos/farmacocinética , Corpo Vítreo/metabolismo
8.
Nat Neurosci ; 10(4): 523-30, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17322875

RESUMO

Most photoactivatable compounds suffer from the limitations of the ultraviolet wavelengths that are required for activation. We synthesized a neuroactive steroid analog with a fluorescent (7-nitro-2,1,3-benzoxadiazol-4-yl) amino (NBD) group in the beta configuration at the C2 position of (3alpha,5alpha)-3-hydroxypregnan-20-one (allopregnanolone, 3alpha5alphaP). Light wavelengths (480 nm) that excite compound fluorescence strongly potentiate GABAA receptor function. Potentiation is limited by photodepletion of the receptor-active species. Photopotentiation is long-lived and stereoselective and shows single-channel hallmarks similar to steroid potentiation. Other NBD-conjugated compounds also generate photopotentiation, albeit with lower potency. Thus, photopotentiation does not require a known ligand for neurosteroid potentiating sites on the GABAA receptor. Photoactivation of a membrane-impermeant, fluorescent steroid analog demonstrates that membrane localization is critical for activity. The photoactivatable steroid silences pathological spiking in cultured rat hippocampal neurons and anesthetizes tadpoles. Fluorescent steroids photoactivated by visible light may be useful for modulating GABAA receptor function in a spatiotemporally defined manner.


Assuntos
Anestésicos/farmacologia , Anticonvulsivantes/farmacologia , Fluoresceína , Luz , Pregnanolona/farmacologia , Animais , Animais Recém-Nascidos , Linhagem Celular Transformada , Hipocampo/citologia , Humanos , Larva/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Potenciais da Membrana/efeitos da radiação , Neurônios/efeitos dos fármacos , Técnicas de Patch-Clamp , Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Subunidades Proteicas/genética , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade , Natação , Transfecção , Ácido gama-Aminobutírico/farmacologia
9.
J Med Chem ; 49(11): 3225-34, 2006 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-16722640

RESUMO

A GABA(A) receptor study of several B-nor analogues of allopregnanolone and pregnanolone has been carried out. B-norallopregnanolone (i.e., 3alpha-hydroxy-7-nor-5alpha-pregnan-20-one) was found comparable to allopregnanolone when measured with labeled TBPS. Analogous results were obtained from their effect on neurons in culture: this time, both 3alpha-hydroxy-7-nor-5xi-pregnan-20-ones (5 and 6) were found to stimulate [3H]flunitrazepam binding and GABA-induced 36Cl- influx. These effects were inhibited by GABA(A) receptor antagonists. Other analogues carrying electronegative substituents (epoxides 9 and 10 and ketone 12) in the B ring were inactive. Similarly, B-normal ketones 17, and 18 and 6-azasteroids 20 and 21 were also inactive. B-Nor analogues 5 and 6 did not induce neurotoxicity at relevant concentrations. A computational analysis of active and inactive neurosteroid analogues allowed the proposal of a 3D pharmacophoric hypothesis of their interaction with the GABA(A) receptor.


Assuntos
Moduladores GABAérgicos/síntese química , Neurônios/efeitos dos fármacos , Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Receptores de GABA-A/efeitos dos fármacos , Animais , Ânions , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cloretos/metabolismo , Simulação por Computador , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Masculino , Modelos Moleculares , Neocórtex/citologia , Neurônios/metabolismo , Pregnanolona/farmacologia , Ensaio Radioligante , Ratos , Ratos Wistar , Receptores de GABA-A/metabolismo , Relação Estrutura-Atividade
10.
Steroids ; 71(1): 77-82, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16246385

RESUMO

The synthesis of biologically active 3alpha-hydroxyl-21-(1'-imidazolyl)-3beta-methoxymethyl-5alpha-pregnan-20-one was accomplished in six steps. The key steps were the improvement of stereoselectivity for acetyl isomers in C-17 and the introduction of imidazole into the core structure by use of lithium imidazole. This latter key step provided the desired product in 82% yield without the formation of 1,3-disubstituted imidazolium salt as impurity, which is generally observed in traditional method.


Assuntos
Pregnanolona/análogos & derivados , Pregnanolona/química , Pregnanolona/síntese química , Hidrogenação , Imidazóis/química , Oxirredução , Temperatura
11.
J Enzyme Inhib Med Chem ; 20(5): 417-28, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16335049

RESUMO

Intraocular neovascularization is a complication in a variety of eye diseases, and is a leading cause of visual loss. The purpose of this study was to design and synthesize three novel codrugs of the antiangiostatic steroid, 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) with the cytotoxic agent 5-fluorouracil (5FU) which incorporates either one or two molecules of 5FU attached through carbonate ester linkages at positions O(3), and/or O(21) of the THS molecule. Furthermore, a kinetic study of the O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyL) 17alpha-hydroxy-5beta-pregnan-20-one (THS-BIS-5FU) codrug was carried out. The overall goal of this codrug strategy was to improve sustained drug delivery of both compounds by overcoming their individual solubility problems, and to thus enhance their bioavailability. The codrug was found to be optimal with superior angiostatic activity using the CAM assay compared to the activity of the parent compounds alone. In the hydrolysis studies 5FU was released at a faster rate than THS with an unknown intermediate observed by HPLC, a rationale and proposed structure and mechanism of the unknown THS derivative is provided.


Assuntos
Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Pregnanolona/análogos & derivados , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Animais , Disponibilidade Biológica , Bovinos , Galinhas , Ciclização , Quimioterapia Combinada , Fluoruracila/farmacologia , Humanos , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Pregnanolona/administração & dosagem , Pregnanolona/síntese química , Pregnanolona/química , Pregnanolona/farmacologia , Solubilidade
12.
J Med Chem ; 48(8): 3051-9, 2005 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-15828844

RESUMO

The planar 5alpha-reduced steroid (3alpha,5alpha)-3-hydroxypregnan-20-one and the nonplanar 5beta-reduced steroid (3alpha,5beta)-3-hydroxypregnan-20-one act at GABA(A) receptors to induce general anesthesia. The structural features of the binding sites for these anesthetic steroids on GABA(A) receptors have not been determined. To determine how structural modifications at the steroid C-6 and C-7 positions effect the actions of these anesthetic steroids, an axial or equatorial methyl group was introduced at these positions. The analogues were evaluated (1) in [(35)S]-tert-butylbicyclophosphorothionate binding experiments, (2) in electrophysiological experiments using rat alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes, and (3) as tadpole anesthetics. The effects of methyl group substitution in the 5alpha- and 5beta-reduced series of compounds were strikingly similar. In both series, a 6beta-Me group gave compounds with actions similar to or greater than those of the parent steroids. A 6alpha-, 7beta- or 7alpha-Me substituent resulted in reduced potency for inhibition of radioligand binding, GABA(A) receptor modulation and tadpole anesthesia. Because of the similar effects of methyl group substitution in the two series of compounds and previous results from other studies showing that structural modifications in the steroid D ring/side chain region produce similar effects regardless of the stereochemistry of the A,B-ring fusion, we propose that either the 3alpha-hydroxyl groups of planar and nonplanar anesthetic steroids hydrogen bond to different amino acids on GABA(A) receptors or that this critical hydrogen bonding group interacts with membrane lipids instead of the receptor.


Assuntos
Anestésicos/síntese química , Moduladores GABAérgicos/síntese química , Pregnanolona/síntese química , Receptores de GABA-A/efeitos dos fármacos , Anestésicos/química , Anestésicos/farmacologia , Animais , Sítios de Ligação , Ligação Competitiva , Encéfalo/metabolismo , Eletrofisiologia , Feminino , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Técnicas In Vitro , Larva , Modelos Moleculares , Oócitos/efeitos dos fármacos , Oócitos/fisiologia , Pregnanolona/química , Pregnanolona/farmacologia , Ensaio Radioligante , Ratos , Receptores de GABA-A/fisiologia , Reflexo/efeitos dos fármacos , Estereoisomerismo , Relação Estrutura-Atividade , Xenopus laevis
13.
Steroids ; 69(3): 161-71, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15072918

RESUMO

Deuterated analogs of pregnenolone and pregnenolone sulfate with three atoms of deuterium in position 19 were prepared. The synthetic approach was developed on derivatives of dehydroepiandrosterone, where initial intermediates were well characterized, and then applied to the pregnenolone series. Starting 19-hydroxy compounds were transformed into 3alpha,5-cycloderivatives to simplify the Jones oxidation into the corresponding 19-oic acids. After oxidation, rearrangement to 3-hydroxy-5-enes, and suitable protection, two deuterium atoms were introduced by lithium aluminum deuteride reduction. Mesylate exchange by iodide in the presence of zinc and deuterium oxide added third deuterium atom. Deprotection gave title analogs with about 93-95% content of d3-derivative, the rest was mainly not fully deuterated d2-analogue as followed from the mass spectra analysis. Thus, 3beta-hydroxy[19-2H3]androst-5-en-17-one was prepared in 14 steps from 19-hydroxy-17-oxoandrost-5-en-3beta-yl acetate in 8.9% yield, the analogous sequence in the pregnenolone series gave 3beta-hydroxy[19-2H3]pregn-5-en-20-one in 7.3% yield. Corresponding sulfates were prepared via pyridinium salts in 53 and 57% yields, respectively. Fully assigned NMR data of selected pregnenolone derivatives were given.


Assuntos
Desidroepiandrosterona/análogos & derivados , Desidroepiandrosterona/síntese química , Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Pregnenolona/síntese química , Androstanos/química , Técnicas de Química Combinatória , Desidroepiandrosterona/química , Deutério/química , Estrutura Molecular , Pregnanolona/química , Pregnenolona/química
14.
J Med Chem ; 46(25): 5334-48, 2003 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-14640542

RESUMO

The hydrogen-bond-acceptor properties of the carbonyl moiety in the 17beta-acetyl group on the D-ring of the anesthetic steroids (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregan-20-one form an important part of the anesthetic steroid pharmacophore. 13,24-Cyclo-18,21-dinorcholanes containing a ketone or conjugated ketone group at C-20, C-22, C-23, or C-24 were prepared as conformationally constrained analogues of these anesthetic steroids and were used to probe for alternate locations for the D-ring hydrogen-bond-accepting carbonyl group. The analogues were evaluated (1). in [(35)S]-tert-butylbicyclophosphorothionate binding experiments, (2). in electrophysiological experiments using rat alpha(1)beta(2)gamma(2L) GABA(A) receptors expressed in Xenopus laevis oocytes, and (3). as tadpole anesthetics. In the binding assay, the relative order of potencies for the analogues in the 5alpha- and 5beta-series is identical. For the ketones, the order is 24-one >or= 23-one > 20-one > 22-one. Likewise, for the enones, the order is delta(22)-24-one > delta(20(22))-23-one > delta(22)-20-one > delta(23)-22-one. Similar relative orders of potencies are also found in the other two bioassays. The activities of the 24-one and delta(22)-24-one compounds were expected to be very low, because the carbonyl group in these compounds is located over the steroid C-ring and oriented toward C-8. Instead, these compounds have the highest activities in their respective series, with the delta(22)-24-one compounds having activities comparable to those of the reference anesthetic steroids. The electrophysiology results obtained with the 24-oxo-cyclosteroids suggest that rat alpha(1)beta(2)gamma(2L) GABA(A) receptors contain more than one donor for the hydrogen-bond-acceptor group of anesthetic steroids. The family of cyclosteroids should be useful for future structure-activity relationship studies of steroid modulation of other GABA(A) receptor subtypes.


Assuntos
Anestésicos/síntese química , Moduladores GABAérgicos/síntese química , Noresteroides/síntese química , Pregnanolona/análogos & derivados , Pregnanolona/síntese química , Anestésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Eletrofisiologia , Feminino , Moduladores GABAérgicos/farmacologia , Técnicas In Vitro , Larva , Modelos Moleculares , Noresteroides/farmacologia , Oócitos , Técnicas de Patch-Clamp , Pregnanolona/farmacologia , Ensaio Radioligante , Ratos , Receptores de GABA-A/efeitos dos fármacos , Receptores de GABA-A/metabolismo , Receptores de GABA-A/fisiologia , Relação Estrutura-Atividade , Xenopus laevis
16.
J Med Chem ; 41(14): 2604-13, 1998 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-9651164

RESUMO

The unnatural enantiomers of dehydroepiandrosterone sulfate (1), pregnenolone sulfate (2), and (3alpha,5beta)-3-hydroxypregnan-20-one sulfate (3), compounds 4-6, respectively, were prepared by total steroid synthesis. The enantioselectivity of the compounds as negative modulators of the GABAA receptors present in cultured rat hippocampal neurons was examined using electrophysiological methods. Enantioselectivity was found for the inhibitory actions of the dehydroepiandrosterone enantiomers. The IC50s for compounds 1 and 4 were 11 +/- 1 and 80 +/- 14 microM, respectively. Little, if any, enantioselectivity was found for the other two pairs of steroid sulfate inhibitors. The IC50s for compounds 2 and 5 were 82 +/- 12 and 76 +/- 27 microM, respectively. The IC50s for compounds 3 and 6 were 39 +/- 7 and 46 +/- 2 microM, respectively. The results suggest that the sites of action for the androstane and pregnane series of steroid sulfate blockers of GABA-mediated current are different. The observed enantioselectivity for the actions of dehydroepiandrosterone sulfate indicates that its inhibitory actions are mediated via a chiral recognition site and provides new evidence in support of the earlier hypothesis that there is a binding site for this compound on GABAA receptors. Conversely, the failure to observe enantioselectivity for the actions of pregnenolone sulfate and steroid sulfate 3 indicates that a chiral recognition site for these steroids does not exist on GABAA receptors and suggests that the effects of these compounds on this receptor's function may arise indirectly as a consequence of steroid-induced membrane perturbation.


Assuntos
Sulfato de Desidroepiandrosterona/síntese química , Moduladores GABAérgicos/síntese química , Pregnanolona/análogos & derivados , Pregnenolona/síntese química , Receptores de GABA-A/efeitos dos fármacos , Animais , Células Cultivadas , Sulfato de Desidroepiandrosterona/química , Sulfato de Desidroepiandrosterona/farmacologia , Moduladores GABAérgicos/química , Moduladores GABAérgicos/farmacologia , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Técnicas de Patch-Clamp , Pregnanolona/síntese química , Pregnanolona/química , Pregnanolona/farmacologia , Pregnenolona/química , Pregnenolona/farmacologia , Ratos , Estereoisomerismo
17.
Steroids ; 59(12): 702-11, 1994 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-7900169

RESUMO

The synthesis of several hydroxylated steroids via conjugate addition of Fleming's silyl-cuprate reagent, (PhMe2Si)2CuLi, a masked hydroxyl group, to the appropriate enone was studied. By this means 7 alpha-hydroxytestosterone (7) was obtained in good yield from 17 beta-hydroxyandrosta-4,6-dien-3-one (1a), though similar reactions on 17 beta-hydroxyandrosta-1,4-dien-3-one (8) gave a low yield of 1 alpha-hydroxytestosterone (13) chiefly through the poor conversion of the phenylsilyl intermediate into the halogenosilane. 3 beta,16 alpha-Dihydroxy-5 alpha-pregnan-20-one (18b) was obtained in a similar manner from 3 beta-hydroxy-5 alpha-pregn-16-en-20-one and 5 alpha-cholestane-1 alpha,3 alpha-diol(17) was produced from the 1-en-3-one (14) via conjugate addition of the silyl group, reduction of the carbonyl function, and oxidative removal of the silyl group.


Assuntos
Colestanol/análogos & derivados , Pregnanolona/análogos & derivados , Testosterona/análogos & derivados , Androstenos/síntese química , Colestanol/síntese química , Cobre/química , Espectroscopia de Ressonância Magnética , Pregnanolona/síntese química , Testosterona/síntese química
18.
Steroids ; 56(11): 544-8, 1991 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-1814019

RESUMO

A method is described for the synthesis and purification of 3 alpha-hydroxy-5 alpha-[1,2-3H]pregnan-20-one. [1,2-3H]progesterone (55 Ci/mmol) was incubated with a homogenate of rat brain tissue. The product was purified by Sephadex chromatography and thin-layer chromatography. The identity and purity of the product were established by successive recrystallizations and high-performance liquid chromatography. A 34% portion of the starting material was converted to 3 alpha-hydroxy-5 alpha-[1,2-3H]pregnan-20-one. The final radiopurity of 3 alpha-hydroxy-5 alpha-pregnan-20-one obtained from four independent preparations was 94% to 99%.


Assuntos
Anestésicos/síntese química , Pregnanolona/síntese química , Anestésicos/isolamento & purificação , Animais , Cromatografia em Gel , Cromatografia em Camada Fina , Masculino , Estrutura Molecular , Pregnanolona/isolamento & purificação , Ratos , Ratos Endogâmicos , Padrões de Referência , Trítio
19.
J Med Chem ; 33(6): 1572-81, 1990 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-2160534

RESUMO

Certain 3 alpha-hydroxy steroids have recently been shown to bind to the gamma-aminobutyric acid (GABA) receptor gated chloride ion channel with high affinity and to potentiate the inhibitory effects of GABA when measured both in vitro and in vivo. In the present study, a series of natural and synthetic 3 alpha-hydroxy steroids were tested for their ability to potentiate GABA-receptor-mediated chloride ion (Cl-) uptake into cerebral cortical synaptoneurosomes. The naturally occurring metabolites 3 alpha-hydroxy-5 alpha-pregnan-20-one (allopregnanolone) and 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydroDOC) were found to be the most active in augmenting GABAA-receptor-mediated Cl- uptake. Pharmacological activity was reduced in the corresponding isomers with the 5 beta-pregnane configuration and by some, but not all, modifications of the side chain. The ability of these steroids to potentiate muscimol-stimulated Cl- uptake is lost by acetylation at C3, introduction of unsaturation at C9(11), inversion to the 3 beta-hydroxy isomer, or inversion of configuration at C17. A facile procedure is reported for the synthesis of unlabeled and tritium-labeled allopregnanolone and allotetrahydroDOC. The 9 alpha,11 alpha,12 alpha-3H-labeled derivatives of allopregnanolone and allotetrahydroDOC were used to identify the distribution and metabolic products of these active steroids. Uptake of the more hydrophobic [3H]allopregnanolone into brain was significantly greater than that of [3H]allotetrahydroDOC. The principal 3H-labeled metabolites recovered from brain were the 3-ketone derivatives of allopregnanolone and allotetrahydroDOC, which are both inactive on GABA-receptor-mediated Cl- flux. Molecular modeling of the active steroids based on quantitative structure-activity relationships provides evidence to support the stereospecificity of the binding interactions and suggests that there may be more than one type of steroid binding site associated with the GABAA-receptor-mediated chloride ionophore.


Assuntos
Cloretos/metabolismo , Desoxicorticosterona/análogos & derivados , Pregnanos/farmacologia , Pregnanolona/farmacologia , Receptores de GABA-A/efeitos dos fármacos , Sinaptossomos/efeitos dos fármacos , Acetatos , Animais , Córtex Cerebral/metabolismo , Desoxicorticosterona/síntese química , Desoxicorticosterona/metabolismo , Desoxicorticosterona/farmacologia , Sinergismo Farmacológico , Isomerismo , Masculino , Conformação Molecular , Muscimol/farmacologia , Pregnanolona/síntese química , Pregnanolona/metabolismo , Ratos , Ratos Endogâmicos , Receptores de GABA-A/fisiologia , Relação Estrutura-Atividade , Sinaptossomos/metabolismo
20.
Steroids ; 45(1): 39-51, 1985 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-4089911

RESUMO

A method for the convenient synthesis of the recently isolated allylic gonadal steroids, 3 alpha-hydroxy-4-pregnen-20-one (3 alpha-dihydroprogesterone; 3 alpha-DHP) and 3 alpha-hydroxy-4-androsten-17-one (3 alpha-HA), was developed using 4-pregnene-3,20-dione (progesterone) and 4-androstene-3,17-dione as substrates and potassium trisiamylborohydride (KS-Selectride) as reducing agent. Similar reactions were also used for the reduction of 5 alpha-pregnane-3,20-dione to 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha-HP). The yields were about 15%, 50%, and greater than 90% for 3 alpha-DHP, 3 alpha-HA and 3 alpha-HP, respectively. Structures of the products, including the 3 beta-isomers and the 17 alpha-epimer, formed in these reactions were determined by NMR and mass spectroscopic methods.


Assuntos
Androsterona/análogos & derivados , Pregnanos/síntese química , Pregnanolona/síntese química , Androstenodiona , Androsterona/síntese química , Cromatografia Gasosa-Espectrometria de Massas , Espectroscopia de Ressonância Magnética , Oxirredução , Progesterona
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