title: Conformationally constrained anesthetic steroids that modulate GABA(A) receptors.
abstract: 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.
authors.affiliation: Research and Development, Organon Laboratories Ltd., Newhouse, Motherwell, Lanarkshire ML1 5SH, Scotland, UK.
authors.forename: A
authors.initials: A
authors.lastname: Anderson
authors.forename: A C
authors.initials: AC
authors.lastname: Boyd
authors.forename: J K
authors.initials: JK
authors.lastname: Clark
authors.forename: L
authors.initials: L
authors.lastname: Fielding
authors.forename: D K
authors.initials: DK
authors.lastname: Gemmell
authors.forename: N M
authors.initials: NM
authors.lastname: Hamilton
authors.forename: M S
authors.initials: MS
authors.lastname: Maidment
authors.forename: V
authors.initials: V
authors.lastname: May
authors.forename: R
authors.initials: R
authors.lastname: McGuire
authors.forename: P
authors.initials: P
authors.lastname: McPhail
authors.forename: F H
authors.initials: FH
authors.lastname: Sansbury
authors.forename: H
authors.initials: H
authors.lastname: Sundaram
authors.forename: R
authors.initials: R
authors.lastname: Taylor
mesh_terms: 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
chemical_list: D000732:Androstanols; D000777:Anesthetics; D018757:GABA Modulators; D011963:Receptors, GABA-A