Anesthetic activity of novel water-soluble 2 beta-morpholinyl steroids and their modulatory effects at GABAA receptors

Journal of Medicinal Chemistry
A AndersonH Sundaram

Abstract

(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 mod...Continue Reading

References

Mar 1, 1975·Anesthesiology·L Gyermek, L F Soyka
Jul 1, 1979·Journal of Steroid Biochemistry·G H PhillipsP J May
May 1, 1975·Journal of Steroid Biochemistry·G H Phillipps
Mar 1, 1987·British Journal of Pharmacology·G A CottrellJ A Peters
Jul 1, 1965·Journal of Medicinal Chemistry·J FinkelsteinJ Lee
Dec 10, 1984·Brain Research·N L Harrison, M A Simmonds
Aug 1, 1981·Pflügers Archiv : European journal of physiology·O P HamillF J Sigworth
Aug 1, 1983·British Journal of Anaesthesia·P TachonJ C Evreux
Sep 1, 1995·Trends in Pharmacological Sciences·J J LambertJ A Peters
Apr 1, 1993·Anesthesiology·D L TanelianM B MacIver
Apr 1, 1996·Trends in Neurosciences·R M McKernan, P J Whiting

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Citations

Mar 27, 2001·Transplantation Proceedings·P GrossiL Minoli
Dec 18, 2001·Brain Research. Brain Research Reviews·J J LambertB G Frenguelli
Dec 18, 2001·Brain Research. Brain Research Reviews·D F CoveyR H Purdy
Apr 11, 2001·Bioorganic & Medicinal Chemistry Letters·A CookeP Vijn
Jun 1, 2002·Bioorganic & Medicinal Chemistry Letters·Masayuki Nakamura, Jun Inoue
Feb 5, 2003·Bioorganic & Medicinal Chemistry Letters·Adriana S VeleiroGerardo Burton
Mar 20, 2003·Bioorganic & Medicinal Chemistry Letters·Andrew CookeHardy Sundaram
Jun 5, 2003·Bioorganic & Medicinal Chemistry Letters·D Jonathan BennettPeter Vijn
Feb 20, 2009·Chemical Communications : Chem Comm·Xianbing KeXianming Hu
Oct 28, 2006·Annual Review of Pharmacology and Toxicology·Meindert DanhofRob A Voskuyl
Oct 22, 2002·The Journal of Pharmacology and Experimental Therapeutics·S A G VisserM Danhof
Oct 29, 2002·Anesthesia and Analgesia·Mariusz G BanaszczykSheldon S Hendler
Dec 4, 2015·Steroids·Alexander KasalMaria Manuel C Silva
Nov 7, 2000·Journal of Medicinal Chemistry·A AndersonR Taylor
Apr 26, 2000·Journal of Medicinal Chemistry·M Chebib, G A Johnston
Feb 1, 2003·The Journal of Organic Chemistry·Daniel OvesVicente Gotor
Oct 8, 2005·The Journal of Organic Chemistry·Fernando J DuranGerardo Burton
Aug 5, 2005·Journal of Medicinal Chemistry·Charikleia SouliManthos Papadopoulos

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