Enaminone amides as novel orally active GABAA receptor modulators.
J Med Chem
; 50(14): 3369-79, 2007 Jul 12.
Article
em En
| MEDLINE
| ID: mdl-17571865
ABSTRACT
A series of enaminone esters and amides have been developed as potent allosteric modulators of gamma-aminobutyric acidA (GABAA) receptors. The compounds bind to a novel modulatory site that is independent of the benzodiazepine (BZ), isosteric GABA, and neuroactive steroid binding sites. Structure-activity relationship (SAR) studies resulted in the synthesis of the c-Bu amide 16h with an in vitro potency of 7 nM based on inhibition of [35S]TBPS binding. The activity of the enaminones as positive allosteric modulators was confirmed with electrophysiological measurements in oocytes expressing alpha1beta2gamma2L GABAA receptors. The i-Pr, s-Bu, c-Pr, and c-Bu amides (16e-h) were orally active in mice with profound central nervous system depressant effects. The i-Pr amide 16e was an orally active anxiolytic in the mouse light-dark paradigm.
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Base de dados:
MEDLINE
Assunto principal:
Receptores de GABA-A
/
Amidas
Limite:
Animals
Idioma:
En
Ano de publicação:
2007
Tipo de documento:
Article