Anesthetic activity of novel water-soluble 2β-morpholinyl steroids and their modulatory effects at GABA(A) receptors

Alison Anderson, Andrew C. Boyd, Alan Byford, Alexander C. Campbell, David K. Gemmell, Niall M. Hamilton, David R. Hill, Claire Hill-Venning, Jeremy J. Lambert, Maurice S. Maidment, Valerie May, Richard J. Marshall, John A. Peters, David C. Rees, Donald Stevenson, Hardy Sundaram

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(3α,5α)-3-Hydroxypregnan-20-ones and (3α,5α)-3-hydroxypregnane- 11,20-diones bearing a 2β-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 (2β,3α,5α)-3- hydroxy-2-(2,2-dimethyl-4-morpholinyl)-pregnane-11,20-dione (19) and (2β,3α,5α)-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 GABA(A) 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 GABA(A) receptors.

Original languageEnglish
Pages (from-to)1668-1681
Number of pages14
JournalJournal of Medicinal Chemistry
Issue number11
Publication statusPublished - 23 May 1997

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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