Characteristics of the association of brotizolam, a thieno-triazolo diazepine derivative, with the benzodiazepine receptor: a selective and high affinity ligand of the central type I benzodiazepine receptor.

Characteristics of the association of brotizolam, a thieno-triazolo diazepine derivative, to central benzodiazepine receptors were examined. Brotizolam significantly displaced the [3H]flunitrazepam and [3H]beta-carboline carboxylate ethylester bindings to crude synaptic membrane from the rat brain. This agent had the highest affinity for benzodiazepine receptors in the cerebellum, and it was found to be 2.1 times that in the spinal cord. Furthermore, a low concentration of brotizolam potentiated the GABA-stimulated 36Cl- influx into membrane vesicles. In contrast, the bindings of [3H]8-hydroxy-2-(di-n-propylamino)tetralin to 5-hydroxytryptamine1A receptors and [3H]ketanserin to 5-hydroxytryptamine2 receptors were not affected by brotizolam. The present results suggest that brotizolam may be a selective and high affinity ligand for the type I central benzodiazepine receptor. The anxiolytic and hypnotic actions of brotizolam seem to be not due to the association with 5-hydroxytryptamine receptor, but due to the activation of the GABAA receptor complex. Furthermore, the present results suggest that the lower affinity of brotizolam to benzodiazepine receptors in the spinal cord than those in the cerebellum may be related to the low muscle relaxation action of this drug.

[1]  J. Taguchi,et al.  Functional modulation of cerebral gamma-aminobutyric acidA receptor/benzodiazepine receptor/chloride ion channel complex with ethyl beta-carboline-3-carboxylate: presence of independent binding site for ethyl beta-carboline-3-carboxylate. , 1990, The Journal of pharmacology and experimental therapeutics.

[2]  P. Seeburg,et al.  Type I and type II GABAA-benzodiazepine receptors produced in transfected cells. , 1989, Science.

[3]  K. Lloyd,et al.  Specificity within the GABAA receptor supramolecular complex: A consideration of the new ω 1-receptor selective imidazopyridine hypnotic zolpidem , 1988, Pharmacology Biochemistry and Behavior.

[4]  B. Longoni,et al.  γ‐Aminobutyric Acid and Pentobarbital Enhance 2‐[3H]Oxoquazepam Binding to Type I Benzodiazepine Recognition Sites in Rat and Human Brain , 1988 .

[5]  I. Martin.  The benzodiazepines and their receptors: 25 years of progress , 1987, Neuropharmacology.

[6]  H. Yamamura,et al.  The effect of benzodiazepines and beta-carbolines on GABA-stimulated chloride influx by membrane vesicles from the rat cerebral cortex. , 1986, Biochemical and biophysical research communications.

[7]  F. Kuhn,et al.  Antiemotional and anticonvulsant activity of brotizolam and its effects on motor performance in animals. , 1986, Arzneimittel-Forschung.

[8]  M. Hamon,et al.  [3H]8‐Hydroxy‐2‐(Di‐n‐Propylamino)Tetralin Binding to Pre‐ and Postsynaptic 5‐Hydroxytryptamine Sites in Various Regions of the Rat Brain , 1985, Journal of neurochemistry.

[9]  R. Harris,et al.  Functional coupling of gamma-aminobutyric acid receptors to chloride channels in brain membranes. , 1985, Science.

[10]  Y. Watanabe,et al.  Ontogenetic properties of benzodiazepine receptor subtypes in rat spinal cord. , 1985, European journal of pharmacology.

[11]  S. Paul,et al.  Pharmacological and neurochemical properties of 1,4-diazepines with two annelated heterocycles ('hetrazepines'). , 1985, European journal of pharmacology.

[12]  R. Squires.  Benzodiazepine receptor multiplicity , 1983, Neuropharmacology.

[13]  C. Braestrup,et al.  Benzodiazepine receptor ligands with positive and negative efficacy , 1983, Neuropharmacology.

[14]  J. Leysen,et al.  [3H]Ketanserin (R 41 468), a selective 3H-ligand for serotonin2 receptor binding sites. Binding properties, brain distribution, and functional role. , 1982, Molecular pharmacology.

[15]  C. Braestrup,et al.  [3H]Propyl β‐Carboline‐3‐Carboxylate as a Selective Radioligand for the BZ1 Benzodiazepine Receptor Subclass , 1981, Journal of neurochemistry.

[16]  R. Olsen.  GABA‐Benzodiazepine‐Barbiturate Receptor Interactions , 1981, Journal of neurochemistry.

[17]  M. Nielsen,et al.  Ethyl β-carboline-3-carboxylate shows differential benzodiazepine receptor interaction , 1980, Nature.

[18]  A. Young,et al.  Gamma-aminobutyric acid binding to receptor sites in the rat central nervous system. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Ikeda,et al.  Relative efficacies of 1,4-diazepines on GABA-stimulated chloride influx in rat brain vesicles. , 1989, Life sciences.

[20]  H. Yamamura,et al.  Modulation of GABA-stimulated chloride influx into membrane vesicles from rat cerebral cortex by triazolobenzodiazepines. , 1988, Life Science.