Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Allosteric Regulation
-
Amino Acids / chemical synthesis*
-
Amino Acids / chemistry
-
Amino Acids / pharmacology
-
Anesthetics, General / chemical synthesis*
-
Anesthetics, General / chemistry
-
Anesthetics, General / pharmacology
-
Animals
-
Brain / metabolism
-
Chromatography, High Pressure Liquid
-
Drug Evaluation, Preclinical
-
Esters
-
GABA Agents / chemical synthesis*
-
GABA Agents / chemistry
-
GABA Agents / pharmacology
-
In Vitro Techniques
-
Male
-
Mice
-
Models, Molecular
-
Oocytes / physiology
-
Phenols / chemical synthesis*
-
Phenols / chemistry
-
Phenols / pharmacology
-
Radioligand Assay
-
Rats
-
Rats, Wistar
-
Receptors, GABA-A / drug effects*
-
Solubility
-
Structure-Activity Relationship
-
Xenopus laevis
Substances
-
2-(N-bis(2-methoxyethyl)amino)butyric acid,2',6'-dimethoxyphenyl ester hydrobromide
-
Amino Acids
-
Anesthetics, General
-
Esters
-
GABA Agents
-
Phenols
-
Receptors, GABA-A