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Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. II. In vitro and in vivo interactions with benzodiazepine binding sites



Tetrazepam: a benzodiazepine which dissociates sedation from other benzodiazepine activities. II. In vitro and in vivo interactions with benzodiazepine binding sites



Journal of Pharmacology and Experimental Therapeutics 245(2): 699-705



Tetrazepam is a 1,4-benzodiazepine (BZD) derivative which, in rodents, appears to have very little sedative and ataxic effects. In an attempt to identify the molecular mechanisms underlying this particular phamacological profile we examined the interaction of tetrazepam with BZD binding sites. Tetrazempam interacted competitively with "central" and "peripheral" BZD biniding sites and exhibited comparable affinities for both sites. Tetrazepam was approximately one-seventh as potent as diazepam at the central receptor and as potent as diazepam at the peripheral binding site. Tetrazepam did not distinguish type I from type II central BZD receptors, as evidenced by comparable affinities for the cerebellular and hippocampal receptors. In vitro autoradiographic studies showed that tetrazepam displaced [3H]flunitrazepam from rat brain membranes without any clear regional specficity. Like all BZD receptor agonists, tetrazepam exhibited a .gamma.-aminobutyric acid shift, a photoaffiity shift and potentiated the binding of 35S-t-butyl-bicyclophosphorothionate to rat brain membranes. However, the latter effect was observed at relatively high contractions of tetrazepam. In vivo, tetrazepam displaced specifically bound [3H]flunitrazepam from mouse brain (ID50, 37 mg/kg p.o. vs 3.5 mg/kg p.o. for diazepam) and from mouse kidney (ID50, 38 mg/kg p.o. vs. 21 mg/kg p.o. for diazepam). It is concluded that tetrazepam is a BZD receptor agonist; the molecular mechanisms which underly the low sedative potential of the drug cannot at present be explained by a particular interaction with either central or peripheral BZD binding sites, but may be related to the drug's relatively weak effect on 35S-t-butyl-bicyclophosphorothionate binding.

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Accession: 006592308

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PMID: 2896795


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