Alpha-amino acid phenolic ester derivatives: novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors
| Autor: | Jeremy J. Lambert, McPhail P, John A. Peters, Sansbury Fh, Muntoni A, Hutchinson Ej, Bennett Dj, Donald F. M. Stevenson, Maurice S. Maidment, Alison Anderson, Feilden H, Miller S, Ross McGuire, Cooke A, Delia Belelli, Buchanan Ki, Casula A, Sundaram H, Gemmell Dk, Hamilton Nm |
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| Rok vydání: | 2001 |
| Předmět: |
Male
Models Molecular GABA Agents Anesthetics General Drug Evaluation Preclinical In Vitro Techniques ORG-25435 Mice Radioligand Assay Structure-Activity Relationship Xenopus laevis Allosteric Regulation Phenols In vivo Drug Discovery medicine Animals Amino Acids Rats Wistar Chromatography High Pressure Liquid chemistry.chemical_classification Chemistry GABAA receptor Hydrobromide Brain Esters Receptors GABA-A Amino acid Rats Biochemistry Mechanism of action Solubility Anesthetic Oocytes Molecular Medicine medicine.symptom medicine.drug |
| Zdroj: | Journal of medicinal chemistry. 44(22) |
| ISSN: | 0022-2623 |
| Popis: | In the search for a novel water-soluble general anesthetic agent the activity of an alpha-amino acid phenolic ester lead, identified from patent literature, was markedly improved. In addition to improving in vivo activity in mice, good in vitro activity at GABA(A) receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo activity was found, supporting a protein-mediated mechanism of action for anesthesia involving allosteric modulation of GABA(A) receptors. alpha-Amino acid phenolic ester 19, as the hydrobromide salt Org 25435, was selected for clinical evaluation since it retained the best overall anesthetic profile coupled with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and recovery from anesthesia at doses of 3 and 4 mg/kg. |
| Databáze: | OpenAIRE |
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