Enaminone Amides As Novel Orally Active Gabaa Receptor Modulators.
From: Department of Pharmacology, School of Medicine, Med Surge 2, University of California-Irvine, Irvine, California 92697, USA. dhogenka@uci.edu
Journal of medicinal chemistry
- Publish Date: Jul 2007
- ISSN: 0022-2623
- Volume: 50
- Issue: 14
- Pages: 3369-79
- Medium: Print
- Language: English
- Citation (JAMA): Hogenkamp Derk J, Johnstone Timothy B C, Huang Jin-Cheng, et al. Enaminone Amides As Novel Orally Active Gabaa Receptor Modulators.. J. Med. Chem. Jul 2007;50:3369-79
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.
Mesh Headings (Keywords): Administration, Oral, Amides, Animals, Magnetic Resonance Spectroscopy, Male, Mice, Rats, Rats, Sprague-Dawley, Receptors, GABA-A, Structure-Activity Relationship
Check for Full Text / PubMed Unique Identifier (PMID): 17571865
This abstract is part of PubMed, a service of the U.S. National Library of Medicine. PubMed includes more than 17 million citations from MEDLINE and other life science journals for biomedical articles. See Copyright and Disclaimers.
Linked medical terms appearing on this page are added by Healia to help readers find more information and are not part of the original PubMed document.
The data herein was last updated on July 8th, 2008 and may not reflect the most current and accurate data available from NLM.