Articles: pregnanolone.
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Molecular pharmacology · Dec 1996
Enantioselectivity of steroid-induced gamma-aminobutyric acidA receptor modulation and anesthesia.
Neuroactive steroids have been postulated to cause anesthesia by binding to unique steroid recognition sites on gamma-aminobutyric acid (GABA) receptors and modulating GABA receptor function. Steroids interact with these sites diastereoselectively, but it is unknown whether steroid sites show enantioselectivity. To address this issue, we synthesized enantiomers to (+)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile and (+)-3alpha-hydroxy-5alpha-pregnan-20-one. ⋯ The correlation between the effects of steroid enantiomers on channel behavior and their effects as anesthetics provides strong evidence that GABA(A) receptors play a predominant role in steroid-induced anesthesia. The enantiomers also provide a tool to probe the relative contributions of direct chloride channel activation versus potentiation of GABA-elicited currents to the induction of anesthesia. Studies examining the effects of combinations of (+)- and (-)-3alpha-hydroxy-5alpha-androstane-17beta-carbonitrile were consistent with the hypothesis that potentiation of GABA-activated currents contributes to steroid-induced anesthesia but indicated that direct steroid activation of GABA(A) receptors is not mechanistically important in producing anesthesia.
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Molecular pharmacology · May 1996
3 alpha-Hydroxy-3 beta-trifluoromethyl-5 alpha-pregnan-20-one (Co 2-1970): a partial agonist at the neuroactive steroid site of the gamma-aminobutyric acidA receptor.
Neuroactive steroids bind to a unique site on the gamma-aminobutyric acidA (GABAA) receptor complex and allosterically modulate the binding of convulsant ([35S]t-butylbicyclophosphorothionate, [35S]TBPS), GABA ([3H]muscimol), and benzodiazepine ([3H]flunitrazepam) site ligands. In rat cortical membranes, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3 alpha, 5 alpha-P) is a full agonist at the steroid site, inhibiting 96% of specific [35S]TBPS binding and enhancing [3H]flunitrazepam and [3H]muscimol binding 95% and 69% above control levels, respectively. In contrast, the synthetic steroid 3 alpha-hydroxy-3 beta-trifluoromethyl-5 alpha-pregnan-20-one (Co 2-1970) has limited efficacy for modulating the binding of [35S]TBPS (44% inhibition), [3H]flunitrazepam (41% enhancement), and [3H]muscimol (< 10% enhancement). ⋯ Co 2-1970 showed limited efficacy potentiation of GABA-evoked chloride currents relative to 3 alpha, 5 alpha-P (28% and 86% of the GABA maximum current, respectively). Moreover, Co 2-1970 produced a concentration-dependent antagonism of the 3 alpha, 5 alpha-P-induced potentiation that was associated with a reduction in the apparent affinity of 3 alpha, 5 alpha-P (11-fold at 10 microM Co 2-1970). Taken together, these data indicate that Co 2-1970 is a partial agonist at the neuroactive steroid site associated with GABAA receptors.
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Randomized Controlled Trial Comparative Study Clinical Trial
[Hemodynamic effects of three different dosages of the induction hypnotic, eltanolone, in coronary surgery patients].
Eltanolone is a new steroid anaesthetic agent that is 5-beta reduced derivative of progesterone. In the present study we investigated the haemodynamic effects of eltanolone or thiopentone in patients scheduled for coronary artery bypass grafting. ⋯ Mean arterial pressure reduction induced by eltanolone is most likely the result of the combination of a decrease in cardiac contractility and peripheral vasodilatation. In contrast, mean arterial pressure reduction in the case of thiopentone seems to be exclusively related to the negative inotropic properties of the drug. Results of a dosage finding study [5] with eltanolone revealed an AD50 of 0.33 mg/kg. In our study 0.5 mg/kg eltanolone brought all the patients to sleep within 2 minutes. The haemodynamic results do not show any significant difference up to twofold dosage. Therefore, the therapeutic margin seems to be large. Because of considerable interindividual variability additional studies in larger collectives are required for definitive evaluation of the drug.
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Hormones and behavior · Mar 1996
Allopregnanolone (THP) mediates anesthetic effects of progesterone in rat brain.
Intravenous infusion of the progesterone or that of progesterone 5 alpha-reduced metabolite, 3 alpha-hydroxy-5 alpha-pregnan-20-one (THP), induces the loss of righting reflex in freely moving rats at the doses of 49 +/- 15 mg/kg or 5.6 +/- 2.2 mg/kg, respectively. The recovery time of righting reflex was 71 +/- 12 min and 21 +/- 5 min for progesterone and THP, respectively. The time course of brain concentrations of THP, but not that of progesterone, correlated with the loss and the recovery of righting reflex. ⋯ Following progesterone infusion brain level of THP in SKF 105111 pretreated rats was 12% that of vehicle-treated control, and the level of progesterone was 160%. No effect of SKF 105111 on brain THP level was detected in animals infused with THP. These results demonstrate that anesthetic effect of progesterone is mediated through its conversion to THP and support the hypothesis that endogenous metabolites of progesterone may be involved in the regulation of behavior in rats.
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The anaesthetic profile of a novel water-soluble aminosteroid, Org 20599 [(2 beta, 3 alpha, 5 alpha)-21-chloro-3-hydroxy-2-(4-morpholinyl)pregnan-20-one methanesulphonate], and the ability of the compound to allosterically regulate the activity of the GABAA receptor, have been studied in comparison to the properties of established intravenous general-anaesthetic agents. Intravenously administered Org 20599 produced a rapid onset, short duration loss of the righting reflex in mice. The anaesthetic potency of Org 20599 was comparable to that of the steroids 5 alpha-pregnan-3 alpha-ol-20-one or alphaxalone, and exceeded that of propofol, thiopentone or pentobarbitone. ⋯ Such direct agonism varied greatly in maximal effect between compounds. The modulatory and direct agonist actions of Org 20599 were additionally confirmed utilizing rat hippocampal neurones in culture. The results indicate Org 20599 to be a potent and short-acting intravenous anaesthetic agent in mice and suggest positive allosteric regulation of GABAA receptor function to be a plausible molecular mechanism of action for the drug.