Benzodiazepine-binding sites

A class of sedative/hypnotic type drug that exert their effects through the benzodiazepine binding site on GABAa receptors. The class consists both of molecules that contain the benzodiazepine moiety, for example diazepam, lorazepam and flunitrazepam, and the newer, non-benzodiazepine compounds such as zolpidem, zopiclone, indiplon and zaleplon. BzRAs are primarily used for the treatment of anxiety, insomnia and to elicit varying levels of sedation. The wide selection of compounds currently available affords the prescribing clinician extensive options in terms of relative efficacies and durations of action. 

Atack JR Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site. Curr Drug Target CNS Neurol Disord 2 213—232, 2003... 

Awad, M and Gavish, M (1987) Binding of [ H]Ro 5-4864 and [ H]PK 11195 to cerebral cortex and peripheral tissues of various species species differences and heterogeneity in peripheral benzodiazepine binding sites. J. Neurochem. 49 1407-1414. 

Drugan, RC, Basile, AS, Crawley, JN, Paul, SM and Skolnick, P (1987) Peripheral benzodiazepine binding sites in the Maudsley Reactive rat selective decrease confined to peripheral tissues. Brain Res. Bull. 18 143-145. 

Duggan, MJ and Stephenson, FA (1988) Benzodiazepine binding site heterogeneity in the purified GABAa receptor. Eur. J. Pharmacol. 154 293-298. 

Sigel, E. Buhr, A. (1997). The benzodiazepine binding site of GABAA receptors. Trends Pharmacol. Sci. 18, 425-9. 

Davies LP, Drew CA, Duffield P, Johnston GA, Jamieson DD. (1992). Kava pyrones and resin studies on GABAA, GABAB and benzodiazepine binding sites in rodent brain. Pharmacol Toxicol. 71(2) 120-26. 

A series of tubes containing assay buffer (50 mM Tris/HCl, 150 mM KCl, pH 7.4), radioiabeiied benzodiazepine (typically 0-50 nM) and bovine brain membranes (final concentration 0.5 mg/ml or approximately 1 nM in benzodiazepine binding sites) is set up. Nonspecific binding is determined in the presence of an excess of unlabelled benzodiazepine. As some benzodiazepines are light sensitive, we usually use opaque amber tubes for these assays. 

Teissere JA, Czajkowski C. 2001. A p-strand in the y2 subunit lines the benzodiazepine binding site of the GABAa... 

The effects of benzodiazepines, and drugs with similar actions, result from interactions with benzodiazepine binding sites on the GABAa receptor com-... 

The benzodiazepines bind with high affinity to specific macromolecules within the central nervous system. These benzodiazepine-binding sites (receptors) are closely associated with the receptors for j-aminobutyric... 

The primary action of the benzodiazepines as anticonvulsants is to enhance inhibition through their interaction with the GABAa receptor at the benzodiazepine binding site. However, there appears to be an additional action of benzodiazepines blocking voltage-dependent sodium channels. This effect is not seen at usual doses but is likely a factor in their use in the treatment of status epilepticus (discussed later). 

D. Diorio, S.A. Weiner, R.F. Butterworth, M.J. Meaney, B.E. Suranyi-Cadotte, Peripheral benzodiazepine binding sites in Alzheimer s disease frontal and temporal cortex, Neurobiol. Aging 12 (1991) 255-258. 

G.W. Price, R.G. Ahier, S.P. Hume, R. Myers, L. Manjil, J.E. Cremer, S.K. Luthra, C. Pascali, V. Pike, R.S.J. Frackowiak, In vivo binding to peripheral benzodiazepine binding sites in lesioned rat brain Comparison between [ H]PK11195 and f F] PK14105 as markers for neuronal damage, J. Neurochem. 55 (1990) 175-185. 

The GABA-A receptor (Fig. 4.4) constitutes an example of an ionotropic receptor. It is composed of five different protein subunits two alpha-1, two beta-2 and one gamma-2 and is therefore called a pentamer. The benzodiazepine binding site is located at the al/y2 interphase, whereas the activation sites for GABA are located at the al/p2 inteiphase. Once a benzodiazepine molecule has bound, the receptor will change its shape so that it responds more to GABA. Upon activation of the GABA-A receptor the ion channel opens and chloride ions can pass. 

An interaction between G. biloba administered as 80 mg leaf extract twice a day and low-dose trazodone (20 mg twice daily) was suspected in a patient with Alzheimer s disease, who took the two products together. It is postulated that a pharmacodynamic (increased gamma-aminobutyric acid-ergic activity) and pharmacokinetic mechanisms [increased metabolism of trazodone to w-chlorophenylpiperazine (w -CPP), which acts on the benzodiazepine-binding sites and releases gamma-aminobutyric acid] contribute to the observed effect (32). Table 2 provides a list of reported pharmacodynamic and pharmacokinetic interactions involving ginkgo. 

The components of the GABAa receptor-chloride ion channel macromolecule that function as benzodiazepine binding sites... 

Flumazenil is one of several 1,4-benzodiazepine derivatives with a high affinity for the benzodiazepine binding site on the GABAa receptor that act as competitive antagonists. It blocks many of the actions of benzodiazepines, zolpidem, zaleplon,... 

Antagonist at benzodiazepine binding sites on the GABAa receptor... 

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