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Titolo:
NEUROSTEROID ANALOGS - 6 - THE SYNTHESIS AND GABA(A) RECEPTOR PHARMACOLOGY OF ENANTIOMERS OF DEHYDROEPIANDROSTERONE-SULFATE, PREGNENOLONE SULFATE, AND (3-ALPHA,5-BETA)-3-HYDROXYPREGNAN-20-ONE SULFATE
Autore:
NILSSON KR; ZORUMSKI CF; COVEY DF;
Indirizzi:
WASHINGTON UNIV,SCH MED,DEPT MOL BIOL & PHARMACOL,660 S EUCLID AVE STLOUIS MO 63110 WASHINGTON UNIV,SCH MED,DEPT MOL BIOL & PHARMACOL ST LOUIS MO 63110 WASHINGTON UNIV,SCH MED,DEPT PSYCHIAT ST LOUIS MO 63110 WASHINGTON UNIV,SCH MED,DEPT ANAT & NEUROBIOL ST LOUIS MO 63110
Titolo Testata:
Journal of medicinal chemistry
fascicolo: 14, volume: 41, anno: 1998,
pagine: 2604 - 2613
SICI:
0022-2623(1998)41:14<2604:NA-6-T>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
METHYL-D-ASPARTATE; HIPPOCAMPAL CA1 NEURONS; A RECEPTOR; SIGMA-RECEPTORS; STEROIDS; POTENTIATION; PROGESTERONE; ANTAGONIST; MODULATE; CURRENTS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
46
Recensione:
Indirizzi per estratti:
Citazione:
K.R. Nilsson et al., "NEUROSTEROID ANALOGS - 6 - THE SYNTHESIS AND GABA(A) RECEPTOR PHARMACOLOGY OF ENANTIOMERS OF DEHYDROEPIANDROSTERONE-SULFATE, PREGNENOLONE SULFATE, AND (3-ALPHA,5-BETA)-3-HYDROXYPREGNAN-20-ONE SULFATE", Journal of medicinal chemistry, 41(14), 1998, pp. 2604-2613

Abstract

The unnatural enantiomers of dehydroepiandrosterone sulfate (1), pregnenolone sulfate (2), and (3 alpha,5 beta)-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 GABA(A) receptors present in cultured rat hippocampal neurons was examined using electrophysiological methods. Enantioselectivitywas found for the inhibitory actions of the dehydroepiandrosterone enantiomers, The IC(50)s for compounds 1 and 4 were 11 +/- 1 and 80 +/- 14 mu M, respectively. Little, if any, enantioselectivity was found for the other two pairs of steroid sulfate inhibitors. The IC(50)s for compounds 2 and 5 were 82 +/- 12 and 76 +/- 27 mu M, respectively. The IC(50)s for compounds 3 and 6 were 39 +/- 7 and 46 +/- 2 mu M, respectively. The results suggest that the sites of action for the androstaneand 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 insupport of the earlier hypothesis that there is a binding site for this compound on GABA(A) receptors. Conversely, the failure to observe enantioselectivity for the actions of pregnenolone sulfate and steroid sulfate 3 indicates that a chiral recognition site far these steroids does not exist on GABA(A) 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.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 14/07/20 alle ore 09:04:53