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

doi:10.1021/jm010903i

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

DArcy Thompson Unit

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

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 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. 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 language	English
Pages (from-to)	3582-3591
Number of pages	10
Journal	Journal of Medicinal Chemistry
Volume	44
Issue number	22
Early online date	14 Sept 2001
DOIs	https://doi.org/10.1021/jm010903i
Publication status	Published - 25 Oct 2001

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1021/jm010903i

Cite this

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 gaba_a receptors. Journal of Medicinal Chemistry, 44(22), 3582-3591. https://doi.org/10.1021/jm010903i

@article{f646c80ea1584b8693f16821e0f84962,

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

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.",

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

year = "2001",

month = oct,

day = "25",

doi = "10.1021/jm010903i",

language = "English",

volume = "44",

pages = "3582--3591",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "22",

}

Anderson, A, Belelli, D, Bennett, J, Buchanan, KI, Casula, A, Cooke, A, Feilden, H, Gemmell, DK, Hamilton, NM, Hutchinson, EJ, Lambert, JJ, Maidment, MS, McGuire, R, McPhail, P, Miller, S, Muntoni, A, Peters, JA, Sansbury, FH, Stevenson, D & Sundaramt, H 2001, 'α-amino acid phenolic ester derivatives: Novel water-soluble general anesthetic agents which allosterically modulate gaba_a receptors', Journal of Medicinal Chemistry, vol. 44, no. 22, pp. 3582-3591. https://doi.org/10.1021/jm010903i

TY - JOUR

T1 - α-amino acid phenolic ester derivatives

T2 - Novel water-soluble general anesthetic agents which allosterically modulate gabaa receptors

AU - Anderson, Alison

AU - Belelli, Delia

AU - Bennett, Jonathan

AU - Buchanan, Kirsteen I.

AU - Casula, Anna

AU - Cooke, Andrew

AU - Feilden, Helen

AU - Gemmell, David K.

AU - Hamilton, Niall M.

AU - Hutchinson, Edward J.

AU - Lambert, Jeremy J.

AU - Maidment, Maurice S.

AU - McGuire, Ross

AU - McPhail, Petula

AU - Miller, Susan

AU - Muntoni, Annalisa

AU - Peters, John A.

AU - Sansbury, Francis H.

AU - Stevenson, Donald

AU - Sundaramt, Hardy

PY - 2001/10/25

Y1 - 2001/10/25

N2 - 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.

AB - 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.

U2 - 10.1021/jm010903i

DO - 10.1021/jm010903i

M3 - Article

C2 - 11606122

AN - SCOPUS:0035950078

SN - 0022-2623

VL - 44

SP - 3582

EP - 3591

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 22