α-amino acid phenolic ester derivatives: Novel water-soluble general anesthetic agents which allosterically modulate gabaa receptors

Alison Anderson, Delia Belelli, Jonathan Bennett, Kirsteen I. Buchanan, Anna Casula, Andrew Cooke, Helen Feilden, David K. Gemmell, Niall M. Hamilton, Edward J. Hutchinson, Jeremy J. Lambert, Maurice S. Maidment, Ross McGuire, Petula McPhail, Susan Miller, Annalisa Muntoni, John A. Peters, Francis H. Sansbury, Donald Stevenson, Hardy Sundaramt

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Abstract

In the search for a novel water-soluble general anesthetic agent the activity of an α-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 GABAA 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 GABAA receptors. α-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.

Original languageEnglish
Pages (from-to)3582-3591
Number of pages10
JournalJournal of Medicinal Chemistry
Volume44
Issue number22
Early online date14 Sep 2001
DOIs
Publication statusPublished - 25 Oct 2001

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    Anderson, A., Belelli, D., Bennett, J., Buchanan, K. I., Casula, A., Cooke, A., Feilden, H., Gemmell, D. K., Hamilton, N. M., Hutchinson, E. J., Lambert, J. J., Maidment, M. S., McGuire, R., McPhail, P., Miller, S., Muntoni, A., Peters, J. A., Sansbury, F. H., Stevenson, D., & Sundaramt, H. (2001). α-amino acid phenolic ester derivatives: Novel water-soluble general anesthetic agents which allosterically modulate gabaa receptors. Journal of Medicinal Chemistry, 44(22), 3582-3591. https://doi.org/10.1021/jm010903i