Convulsant potencies of tetrazoles are highly correlated with actions on GABA/benzodiazepine/picrotoxin receptor complexes in brain |
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Authors: | R F Squires E Saederup J N Crawley P Skolnick S M Paul |
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Affiliation: | 1. Rockland Research Institute, Orangeburg, New York 10962, USA;2. Clinical Neuroscience Branch, NIMH, National Institutes of Health, Bethesda, Maryland 20205, USA;3. Laboratory of Bioorganic Chemistry, NIADDKD, National Institutes of Health, Bethesda, Maryland 20205, USA |
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Abstract: | A series of tetrazole convulsants were examined for their potencies in displacing [35S]-t-butylbicyclophosphorothionate (TBPS) from the picrotoxin site on the benzodiazepine-GABA-chloride ionophore receptor complex. All of the tetrazole derivatives tested inhibited [35S]-TBPS binding from rat forebrain membranes, and except for one (undecamethylenetetrazole), had Hill coefficients near unity. Similar to other chemically unrelated convulsants the inhibition of [35S]-TBPS binding by the various tetrazole derivatives was unaffected by the addition of the bicucculine-like GABA antagonist, R 5135. To ascertain whether the inhibition of specific [35S]-TBPS binding by the tetrazole derivatives was related to their convulsant properties, we compared their in vitro potencies in displacing [35S]-TBPS binding with their minimum convulsant potencies in mice. A very good correlation was observed (r = 0.96, p less than 0.001) between their relative affinities for the [35S]-TBPS binding site and their convulsant potencies, indicating that pentamethylenetetrazol and related tetrazoles may produce their convulsant and anxiogenic actions via the GABA-benzodiazepine-chloride ionophore receptor complex. |
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Keywords: | Address correspondence and reprint requests to: Dr. S.M. Paul Building 10 Room 4N214 9000 Rockville Pike Bethesda MD 20205 USA |
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