alpha-amino acid phenolic ester derivatives: Novel water-soluble general anesthetic agents which allosterically modulate GABA(A) receptors

In the search for a novel water-soluble general anesthetic agent the activi ty of an a-amino acid phenolic ester lead, identified from patent literatur e, was markedly improved. In addition to improving in vivo activity in mice , good in vitro activity at GABAA receptors was also conferred. Within the series of compounds good enantioselectivity for both in vitro and in vivo a ctivity was found, supporting a protein-mediated mechanism of action for an esthesia involving allosteric modulation of GABAA receptors. a-Amino acid p henolic ester 19, as the hydrobromide salt Org 25435, was selected for clin ical evaluation since it retained the best overall anesthetic profile coupl ed with improved stability and water solubility. In the clinic it proved to be an effective intravenous anesthetic in man with rapid onset of and reco very from anesthesia at doses of 3 and 4 mg/kg.