Conformationally constrained anesthetic steroids that modulate GABA(A) receptors.
Various cyclic ether and other 3 alpha-hydroxyandrostane derivatives bearing a conformationally constrained hydrogen-bonding moiety were prepared. Their anesthetic potency and their binding affinity for GABA(A) receptors, measured by intravenous administration to mice and inhibition of [(35)S]TBPS binding to rat whole brain membranes, were compared with that of known anesthetic 3 alpha-hydroxypregnan-20-ones. Synthetic steroids with similar in vitro and in vivo activities to the endogenous 3 alpha-hydroxypregnan-20-ones all had an ether oxygen on the beta-face of the steroid D-ring. These results suggest that for optimal GABA(A) receptor modulation, the hydrogen bond-accepting substituent should be near perpendicular to the plane of the D-ring on the beta-face of the steroid.
Anderson
A
A
Research and Development, Organon Laboratories Ltd., Newhouse, Motherwell, Lanarkshire ML1 5SH, Scotland, UK.
Boyd
A C
AC
Clark
J K
JK
Fielding
L
L
Gemmell
D K
DK
Hamilton
N M
NM
Maidment
M S
MS
May
V
V
McGuire
R
R
McPhail
P
P
Sansbury
F H
FH
Sundaram
H
H
Taylor
R
R
D000732:Androstanols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000777:Anesthetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000378:metabolism; D018757:GABA Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006860:Hydrogen Bonding; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D051379:Mice; D008958:Models, Molecular; D011869:Radioligand Assay; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000732:Androstanols; D000777:Anesthetics; D018757:GABA Modulators; D011963:Receptors, GABA-A