Action of Some Steroids on the Central Nervous System of the Mouse. II. Pharmacology

Atkinson, R. M.; Davis, BG; Pratt, M. A.; Sharpe, Helen M.; Tomich, E. G.

doi:10.1021/jm00328a004

Cited by 82 publications

(29 citation statements)

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“…McCarthy, Chen, Kaump & Ensor (1965) reported similar effects with ketamine in dogs anaesthetized with pentobarbitone or chloralose. The 'mutual potentiation' between hydroxydione and chloralose in cats was confirmed by Davis (unpublished observations), who further observed potentiation between the steroid anaesthetic 3a-hydroxy-5,8-pregnane-11,20-dione 3-disodium phosphate (Atkinson, Davis, Pratt, Sharpe & Tomich, 1965) Bache, McHale, Curry, Alexander & Greenfield, 1970). However, cats were used in these experiments because the dog is exceptional in exhibiting an anaphylactoid reaction to the polymeric constituent of the vehicle used in the formulation of both propanidid (Wirth & Hoffmeister, 1965) and CT 1341 (Child et al, 1971).…”

Section: Discussionmentioning

confidence: 74%

Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: a comparison with other intravenous anaesthetic drugs in the unrestrained cat

Child¹,

Davis²,

Dodds³

et al. 1972

British J Pharmacology

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Summary1. The anaesthetic, cardiovascular, respiratory and adverse effects produced by the intravenous injection of CT 1341, thiopentone, methohexitone, pentobarbitone, propanidid and ketamine have been compared in unrestrained cats prepared with chronically implanted venous and arterial cannulae. Aortic blood pressure and heart rates were monitored before, during and after loss of consciousness. 2. CT 1341 produced rapid induction of anaesthesia followed by moderately rapid recovery, was active over a wide range of doses and caused minimal respiratory depression and few adverse effects. It caused an initial shortlasting tachycardia and fall in aortic blood pressure succeeded by a secondary depressor response. 3. The safety margin was narrower with the barbiturate drugs than with CT 1341, and large doses induced apnoea and respiratory depression. Small doses of methohexitone elicited excitatory effects and large doses caused severe respiratory and circulatory depression, and recovery from anaesthesia was protracted. 4. Propanidid induced short-lasting light anaesthesia. The safety margin was narrowest with this drug and induction was associated with adverse circulatory, respiratory and other effects. 5. Ketamine was active over a wide range of doses but exhibited qualitatively different properties from the other anaesthetics. Induction was slower after small doses and these produced circulatory stimulation, catatonia and bizarre behavioural effects. Large doses caused respiratory and circulatory depression and recovery was protracted. 6. It is concluded that CT 1341 has a wider therapeutic latitude, produces less respiratory depression and has other advantages over the currently used intravenous anaesthetics.

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Section: Discussionmentioning

confidence: 74%

Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: a comparison with other intravenous anaesthetic drugs in the unrestrained cat

Child¹,

Davis²,

Dodds³

et al. 1972

British J Pharmacology

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“…Certain endogenous pregnane steroids, termed neurosteroids, are potent sedative, anxiolytic, and anesthetic agents in vertebrates (Selye, 1941;Atkinson et al, 1965;Gyermek and Soyka, 1975). There is substantial evidence that the neurobiological effects of neurosteroids are mediated through direct binding interactions with GABA A receptors, the major inhibitory neurotransmitter receptors in the nervous system.…”

Section: Introductionmentioning

confidence: 99%

Neurosteroid Analog Photolabeling of a Site in the Third Transmembrane Domain of the β3 Subunit of the GABAA Receptor

Chen

Manion

Townsend

et al. 2012

Molecular Pharmacology

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Accumulated evidence suggests that neurosteroids modulate GABA A receptors through binding interactions with transmembrane domains. To identify these neurosteroid binding sites directly, a neurosteroid-analog photolabeling reagent, (3␣,5␤)-6-azipregnanolone (6-AziP), was used to photolabel membranes from Sf9 cells expressing high-density, recombinant, His 8 -␤3 homomeric GABA A receptors. 6-AziP inhibited 3 H](3␤,5␤)-6-AziP. Highresolution mass spectrometric analysis of affinity-purified, 6-AziPlabeled His 8 -␤3 subunits identified a single photolabeled peptide, ALLEYAF-6-AziP, in the third transmembrane domain. The identity of this peptide and the site of incorporation on Phe301 were confirmed through high-resolution tandem mass spectrometry. No other sites of photoincorporation were observed despite 90% sequence coverage of the whole ␤3 subunit protein, including 84% of the transmembrane domains. This study identifies a novel neurosteroid binding site and demonstrates the feasibility of identifying neurosteroid photolabeling sites by using mass spectrometry.

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“…The therapeutic index (LD,,/AD,,) was calculated as 8. 4 for pregnanolone emulsion and 19.3 for Althesin ( Table 1).…”

Section: Resultsmentioning

confidence: 99%

Pregnanolone emulsion

Høgskilde

Carl

et al. 1987

Anaesthesia

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Action of Some Steroids on the Central Nervous System of the Mouse. II. Pharmacology

Cited by 82 publications

References 0 publications

Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: a comparison with other intravenous anaesthetic drugs in the unrestrained cat

Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341: a comparison with other intravenous anaesthetic drugs in the unrestrained cat

Neurosteroid Analog Photolabeling of a Site in the Third Transmembrane Domain of the β3 Subunit of the GABAA Receptor

Pregnanolone emulsion

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