Synthesis, Pharmacology, and Structure-activity Relationships of Novel Imidazolones and Pyrrolones As Modulators of Gabaa Receptors.
From: elbion AG, Meissner Strasse 191, D-01445 Radebeul, Germany, and Institute of Biochemistry, Faculty of Biosciences, Pharmacy and Psychology, University of Leipzig, Brüderstrasse 34, D-04103 Leipzig, Germany. christian.grunwald@elbion.de
Journal of medicinal chemistry
- Publish Date: Mar 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 6
- Pages: 1855-66
- Medium: Print
- Language: English
- Citation (JAMA): Grunwald Christian, Rundfeldt Chris, Lankau Hans-Joachim, et al. Synthesis, Pharmacology, and Structure-activity Relationships of Novel Imidazolones and Pyrrolones As Modulators of Gabaa Receptors.. J. Med. Chem. Mar 2006;49:1855-66
Abstract
New series of imidazolones and pyrrolones were synthesized. The compounds were tested regarding their anxiolytic properties due to modulation of the GABAA receptor response. Several derivatives exhibit considerable pharmacological activity while lacking the typical side effects of benzodiazepine receptor agonists. 1-(4-chlorophenyl)-4-morpholin-1-yl-1,5-dihydro-imidazol-2-one (2) and 1-(4-chlorophenyl)-4-piperidin-1-yl-1,5-dihydro-imidazol-2-one (3) were protective in the pentylenetetrazole test in rats with oral ED50 of 27.4 and 12.8 mg/kg and TD50 (rotarod) of >500 and 265 mg/kg, respectively. The minimum effective dose in the Vogel conflict test was 3 mg/kg for both compounds. Common structure-activity relationship and comparative molecular field analysis models of the various series of derivatives could be established which are in accordance with a GABAA mediated pharmacological action. The findings fit well into an established pharmacophore model. This model is refined by an additional steric restriction feature.
Mesh Headings (Keywords): Administration, Oral, Animals, Anti-Anxiety Agents, Anticonvulsants, Binding Sites, Brain, GABA Antagonists, Imidazoles, Male, Mice, Models, Molecular, Morpholines, Pentylenetetrazole, Piperidines, Pyrroles, Quantitative Structure-Activity Relationship, Radioligand Assay, Rats, Rats, Wistar, Receptors, GABA-A, Rotarod Performance Test, Seizures
Check for Full Text / PubMed Unique Identifier (PMID): 16539371
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