Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity

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The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by pReviously prepared allopregnanolone with a 16α -bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 1...

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Autores principales:	Slavíková, B., Krištofíková, Z., Chodounská, H., Buděšínský, M., Durán, F.J., Veleiro, A.S., Burton, G., Kasal, A.
Formato:	JOUR
Materias:	16alpha bis(carbamoyloxymethyl)methyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha carbamoyloxyethyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha ethyl 20 oxo 5alpha pregnane 3alpha,16b diyl dicarbamate 16alpha ethyl 20 oxo 5alpha pregnane 3r,16b diyl dicarbamate 20,20 ethylenedioxy 16r bis(methoxycarbonyl)methyl 5alpha pregnan 3alpha ol 3alpha hydroxy 16alpha (2 hydroxyethoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha (2,3 dihydroxypropoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha [2 hydroxy (2 ethoxyethoxy)] 5alpha pregnan 20 one 3alpha hydroxy 16alpha bis(methoxycarbonyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha methoxycarbonylmethyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha-bis(hydroxymethyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 5alpha pregnan 20 one 3alpha tert butyldimethylsilyloxy 16alpha ethyl 20,20 ethylenedioxy 5alpha pregnan 16b ol 3alpha tert butyldimethylsilyloxy 20,20 ethylenedioxy 16alpha bis(hydroxymethyl)methyl 5alpha pregnane 3beta hydroxy 16ralpha (2' hydroxyethoxy) pregn 5 en 20 one 3r tert butyldimethylsilyloxy 20,20 ethylenedioxy 16r bis (methoxycarbonyl)methyl 5alpha pregnane 4 aminobutyric acid A receptor unclassified drug benzodiazepine receptor affecting agent drug derivative eltanolone article binding site drug activity drug binding drug structure drug synthesis animal brain in vitro study male metabolism radioassay rat structure activity relation synthesis Wistar rat Animals Brain GABA Modulators Male Pregnanolone Radioligand Assay Rats Rats, Wistar Receptors, GABA-A Structure-Activity Relationship
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00222623_v52_n7_p2119_Slavikova
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00222623_v52_n7_p2119_Slavikova
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spelling	todo:paper_00222623_v52_n7_p2119_Slavikova2023-10-03T14:30:16Z Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity Slavíková, B. Krištofíková, Z. Chodounská, H. Buděšínský, M. Durán, F.J. Veleiro, A.S. Burton, G. Kasal, A. 16alpha bis(carbamoyloxymethyl)methyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha carbamoyloxyethyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha ethyl 20 oxo 5alpha pregnane 3alpha,16b diyl dicarbamate 16alpha ethyl 20 oxo 5alpha pregnane 3r,16b diyl dicarbamate 20,20 ethylenedioxy 16r bis(methoxycarbonyl)methyl 5alpha pregnan 3alpha ol 3alpha hydroxy 16alpha (2 hydroxyethoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha (2,3 dihydroxypropoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha [2 hydroxy (2 ethoxyethoxy)] 5alpha pregnan 20 one 3alpha hydroxy 16alpha bis(methoxycarbonyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha methoxycarbonylmethyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha-bis(hydroxymethyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 5alpha pregnan 20 one 3alpha tert butyldimethylsilyloxy 16alpha ethyl 20,20 ethylenedioxy 5alpha pregnan 16b ol 3alpha tert butyldimethylsilyloxy 20,20 ethylenedioxy 16alpha bis(hydroxymethyl)methyl 5alpha pregnane 3beta hydroxy 16ralpha (2' hydroxyethoxy) pregn 5 en 20 one 3r tert butyldimethylsilyloxy 20,20 ethylenedioxy 16r bis (methoxycarbonyl)methyl 5alpha pregnane 4 aminobutyric acid A receptor unclassified drug benzodiazepine receptor affecting agent drug derivative eltanolone article binding site drug activity drug binding drug structure drug synthesis animal brain in vitro study male metabolism radioassay rat structure activity relation synthesis Wistar rat Animals Brain GABA Modulators Male Pregnanolone Radioligand Assay Rats Rats, Wistar Receptors, GABA-A Structure-Activity Relationship The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by pReviously prepared allopregnanolone with a 16α -bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16α 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). [35S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABAA 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. © 2009 American Chemical Society. Fil:Durán, F.J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Veleiro, A.S. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Burton, G. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00222623_v52_n7_p2119_Slavikova
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	16alpha bis(carbamoyloxymethyl)methyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha carbamoyloxyethyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha ethyl 20 oxo 5alpha pregnane 3alpha,16b diyl dicarbamate 16alpha ethyl 20 oxo 5alpha pregnane 3r,16b diyl dicarbamate 20,20 ethylenedioxy 16r bis(methoxycarbonyl)methyl 5alpha pregnan 3alpha ol 3alpha hydroxy 16alpha (2 hydroxyethoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha (2,3 dihydroxypropoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha [2 hydroxy (2 ethoxyethoxy)] 5alpha pregnan 20 one 3alpha hydroxy 16alpha bis(methoxycarbonyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha methoxycarbonylmethyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha-bis(hydroxymethyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 5alpha pregnan 20 one 3alpha tert butyldimethylsilyloxy 16alpha ethyl 20,20 ethylenedioxy 5alpha pregnan 16b ol 3alpha tert butyldimethylsilyloxy 20,20 ethylenedioxy 16alpha bis(hydroxymethyl)methyl 5alpha pregnane 3beta hydroxy 16ralpha (2' hydroxyethoxy) pregn 5 en 20 one 3r tert butyldimethylsilyloxy 20,20 ethylenedioxy 16r bis (methoxycarbonyl)methyl 5alpha pregnane 4 aminobutyric acid A receptor unclassified drug benzodiazepine receptor affecting agent drug derivative eltanolone article binding site drug activity drug binding drug structure drug synthesis animal brain in vitro study male metabolism radioassay rat structure activity relation synthesis Wistar rat Animals Brain GABA Modulators Male Pregnanolone Radioligand Assay Rats Rats, Wistar Receptors, GABA-A Structure-Activity Relationship
spellingShingle	16alpha bis(carbamoyloxymethyl)methyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha carbamoyloxyethyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha ethyl 20 oxo 5alpha pregnane 3alpha,16b diyl dicarbamate 16alpha ethyl 20 oxo 5alpha pregnane 3r,16b diyl dicarbamate 20,20 ethylenedioxy 16r bis(methoxycarbonyl)methyl 5alpha pregnan 3alpha ol 3alpha hydroxy 16alpha (2 hydroxyethoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha (2,3 dihydroxypropoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha [2 hydroxy (2 ethoxyethoxy)] 5alpha pregnan 20 one 3alpha hydroxy 16alpha bis(methoxycarbonyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha methoxycarbonylmethyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha-bis(hydroxymethyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 5alpha pregnan 20 one 3alpha tert butyldimethylsilyloxy 16alpha ethyl 20,20 ethylenedioxy 5alpha pregnan 16b ol 3alpha tert butyldimethylsilyloxy 20,20 ethylenedioxy 16alpha bis(hydroxymethyl)methyl 5alpha pregnane 3beta hydroxy 16ralpha (2' hydroxyethoxy) pregn 5 en 20 one 3r tert butyldimethylsilyloxy 20,20 ethylenedioxy 16r bis (methoxycarbonyl)methyl 5alpha pregnane 4 aminobutyric acid A receptor unclassified drug benzodiazepine receptor affecting agent drug derivative eltanolone article binding site drug activity drug binding drug structure drug synthesis animal brain in vitro study male metabolism radioassay rat structure activity relation synthesis Wistar rat Animals Brain GABA Modulators Male Pregnanolone Radioligand Assay Rats Rats, Wistar Receptors, GABA-A Structure-Activity Relationship Slavíková, B. Krištofíková, Z. Chodounská, H. Buděšínský, M. Durán, F.J. Veleiro, A.S. Burton, G. Kasal, A. Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity
topic_facet	16alpha bis(carbamoyloxymethyl)methyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha carbamoyloxyethyl 3alpha hydroxy 5alpha pregnan 20 one 16alpha ethyl 20 oxo 5alpha pregnane 3alpha,16b diyl dicarbamate 16alpha ethyl 20 oxo 5alpha pregnane 3r,16b diyl dicarbamate 20,20 ethylenedioxy 16r bis(methoxycarbonyl)methyl 5alpha pregnan 3alpha ol 3alpha hydroxy 16alpha (2 hydroxyethoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha (2,3 dihydroxypropoxy) 5alpha pregnan 20 one 3alpha hydroxy 16alpha [2 hydroxy (2 ethoxyethoxy)] 5alpha pregnan 20 one 3alpha hydroxy 16alpha bis(methoxycarbonyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha methoxycarbonylmethyl 5alpha pregnan 20 one 3alpha hydroxy 16alpha-bis(hydroxymethyl)methyl 5alpha pregnan 20 one 3alpha hydroxy 5alpha pregnan 20 one 3alpha tert butyldimethylsilyloxy 16alpha ethyl 20,20 ethylenedioxy 5alpha pregnan 16b ol 3alpha tert butyldimethylsilyloxy 20,20 ethylenedioxy 16alpha bis(hydroxymethyl)methyl 5alpha pregnane 3beta hydroxy 16ralpha (2' hydroxyethoxy) pregn 5 en 20 one 3r tert butyldimethylsilyloxy 20,20 ethylenedioxy 16r bis (methoxycarbonyl)methyl 5alpha pregnane 4 aminobutyric acid A receptor unclassified drug benzodiazepine receptor affecting agent drug derivative eltanolone article binding site drug activity drug binding drug structure drug synthesis animal brain in vitro study male metabolism radioassay rat structure activity relation synthesis Wistar rat Animals Brain GABA Modulators Male Pregnanolone Radioligand Assay Rats Rats, Wistar Receptors, GABA-A Structure-Activity Relationship
description	The lipophilic nature of allopregnanolone prevents its user-friendly application in human medicine. On inspiration by pReviously prepared allopregnanolone with a 16α -bound tetraethylammonium salt, an attempt was made to produce allopregnanolone analogues with polar groups introduced into position 16α 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). [35S]TBPS displacement was used to evaluate the products. Several carbamates (but not their parent alcohols) displaced TBPS from the picrotoxin binding site on GABAA 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. © 2009 American Chemical Society.
format	JOUR
author	Slavíková, B. Krištofíková, Z. Chodounská, H. Buděšínský, M. Durán, F.J. Veleiro, A.S. Burton, G. Kasal, A.
author_facet	Slavíková, B. Krištofíková, Z. Chodounská, H. Buděšínský, M. Durán, F.J. Veleiro, A.S. Burton, G. Kasal, A.
author_sort	Slavíková, B.
title	Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity
title_short	Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity
title_full	Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity
title_fullStr	Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity
title_full_unstemmed	Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity
title_sort	allopregnanolone (3α-hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: synthesis and activity
url	http://hdl.handle.net/20.500.12110/paper_00222623_v52_n7_p2119_Slavikova
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Allopregnanolone (3α-Hydroxy-5α-pregnan-20-one) derivatives with a polar chain in position 16α: Synthesis and activity

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