Anesthetic activity of novel water-soluble 2 beta-morpholinyl steroids and their modulatory effects at GABAA receptors.
(3 alpha,5 alpha)-3-Hydroxypregnan-20-ones and (3 alpha,5 alpha)-3-hydroxypregnane-11,20-diones bearing a 2 beta-morpholinyl substituent were synthesized, and the utility of these steroids as anesthetic agents was evaluated through determination of their potency and duration of hypnotic activity in mice after intravenous administration. Alkylation of the morpholinyl substituent or chlorination at C-21 afforded the novel amino steroids (2 beta,3 alpha,5 alpha)-3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2 beta,3 alpha,5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one (37) that were more potent and advantageously produced shorter sleep times than related compounds which were previously reported. Furthermore, salts of these and other amino steroids generally retained good aqueous solubility. In a radioligand binding assay the compounds inhibited the specific binding of [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes, and in an electrophysiological assay they potentiated GABAA receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells. These in vitro results are consistent with the anesthetic activity of the amino steroids being related to their modulatory effects at GABAA receptors.
Anderson
A
A
Scientific Development Group, Oganon Laboratories Ltd., Newhouse, Lanarkshire, Scotland, UK.
Boyd
A C
AC
Byford
A
A
Campbell
A C
AC
Gemmell
D K
DK
Hamilton
N M
NM
Hill
D R
DR
Hill-Venning
C
C
Lambert
J J
JJ
Maidment
M S
MS
May
V
V
Marshall
R J
RJ
Peters
J A
JA
Rees
D C
DC
Stevenson
D
D
Sundaram
H
H
D000758:Anesthesia; D000777:Anesthetics / Q000138:chemical synthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D002838:Chromaffin System / Q000502:physiology; D004553:Electric Conductivity; D004594:Electrophysiology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011277:Pregnanediones / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000502:physiology*; D012995:Solubility; D013329:Structure-Activity Relationship; D014867:Water
C105491:21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one; C106275:3-hydroxy-2-(2,2-dimethyl-4-morpholinyl)pregnane-11,20-dione; D000777:Anesthetics; D019086:Bridged Bicyclo Compounds, Heterocyclic; D009025:Morpholines; D011277:Pregnanediones; D011963:Receptors, GABA-A; D014867:Water; C037476:tert-butylbicyclophosphorothionate