| Abstract
| - (3α,5α)-3-Hydroxypregnan-20-ones and(3α,5α)-3-hydroxypregnane-11,20-diones bearing a2β-morpholinyl substituent were synthesized, and the utility of thesesteroids as anesthetic agentswas evaluated through determination of their potency and duration ofhypnotic activity inmice after intravenous administration. Alkylation of themorpholinyl substituent or chlorinationat 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 producedshorter sleep times than relatedcompounds which were previously reported. Furthermore, salts ofthese and other aminosteroids generally retained good aqueous solubility. In aradioligand binding assay thecompounds inhibited the specific binding of[35S]-tert-butyl bicyclophosphorothionate torat wholebrain membranes, and in an electrophysiological assay they potentiatedGABAA receptor-mediated currents recorded from voltage-clamped bovine chromaffin cells.These in vitro resultsare consistent with the anesthetic activity of the amino steroids beingrelated to theirmodulatory effects at GABAA receptors.
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