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 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.
Anderson
A
A
Organon Research, Newhouse, Lanarkshire ML1 5SH, Scotland, U.K.
Belelli
D
D
Bennett
D J
DJ
Buchanan
K I
KI
Casula
A
A
Cooke
A
A
Feilden
H
H
Gemmell
D K
DK
Hamilton
N M
NM
Hutchinson
E J
EJ
Lambert
J J
JJ
Maidment
M S
MS
McGuire
R
R
McPhail
P
P
Miller
S
S
Muntoni
A
A
Peters
J A
JA
Sansbury
F H
FH
Stevenson
D
D
Sundaram
H
H
D000494:Allosteric Regulation; D000596:Amino Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018681:Anesthetics, General / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004353:Drug Evaluation, Preclinical; D004952:Esters; D018682:GABA Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009865:Oocytes / Q000502:physiology; D010636:Phenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000187:drug effects*; D012995:Solubility; D013329:Structure-Activity Relationship; D014982:Xenopus laevis
C438943:2-(N-bis(2-methoxyethyl)amino)butyric acid,2',6'-dimethoxyphenyl ester hydrobromide; D000596:Amino Acids; D018681:Anesthetics, General; D004952:Esters; D018682:GABA Agents; D010636:Phenols; D011963:Receptors, GABA-A