Brain benzodiazepine receptors

Viel, G.T., Yang, Q., Lundahl, P, Ensing, K., and de Zeeuw, R. A., Size-exclusion chromatographic reconstitution of the bovine brain benzodiazepine receptor. Effects of lipid environment on the binding characteristics, /. Chromatogr. A, 776, 101, 1997... 

Kavvadias D, Monschein VS, Riederer P, Schreier P. Constituents of sage (Salvia officinalis) with in vitro affinity to human brain benzodiazepine receptor. Planta Med 2003 69 113-117. 

Medina JH, Pena C, Levi de Stein M, Wolfman C, Paladini AC Benzodiazepine-like molecules as well as other ligands for the brain benzodiazepine receptors are relatively common constituents of plants. Biochem Biophys Res Com-mun 1989 165 547-553. 

Nielsen M, Frokjaer S, Braestrup C. (1988). High affinity of the naturally-occurring biflavonoid, amentoflavon, to brain benzodiazepine receptors in vitro. Biochem Pharmacol. 37(17) 3285-87. 

Several studies have suggested increased sensitivity of older persons to effects of benzodiazepines (Table 3). For example, midazolam, widely used for rapid sedation for procedures, requires lower doses to reach defined end points of sedation that is attributable to a 59% reduction in the EC50 (the concentration that produces 50% of the maximum effect) and not to changes in pharmacokinetics, as shown in Fig. 3. The reasons for this increased sensitivity are not known. Animal studies have not shown any difference in brain benzodiazepine receptor density or affinity or effects on the associated chloride channel function with ageing. In any event, benzodiazepine doses should be reduced in older patients. 

Tolerance—decreased responsiveness to a drug following repeated exposure—is a common feature of sedative-hypnotic use. It may result in the need for an increase in the dose required to maintain symptomatic improvement or to promote sleep. It is important to recognize that partial cross-tolerance occurs between the sedative-hypnotics described here and also with ethanol (see Chapter 23)—a feature of some clinical importance, as explained below. The mechanisms responsible for tolerance to sedative-hypnotics are not well understood. An increase in the rate of drug metabolism (metabolic tolerance) may be partly responsible in the case of chronic administration of barbiturates, but changes in responsiveness of the central nervous system (pharmacodynamic tolerance) are of greater importance for most sedative-hypnotics. In the case of benzodiazepines, the development of tolerance in animals has been associated with down-regulation of brain benzodiazepine receptors. Tolerance has been reported to occur with the extended use of zolpidem. Minimal tolerance was observed with the use of zaleplon over a 5-week period and eszopiclone over a 6-month period. 

The influence of structural features of benzodioxepine and benzodithiepine derivatives on rat brain benzodiazepine receptors has been studied <1996MSR589>. A group at Givaudan has synthesized and studied the conception, characterization, and correlation of new marine odorants based on the benzo[A][l,4]dioxepinone system <2003EJO3735>. 1,4-Dithiapane was among a data set of 101 hetero sulfamate sodium salts that was tested as potential sweeteners in a structure-taste relationship study <2000J(P2)1369>. 

Rehnberg, B.G., E.H. Bates, R.J. Smith, B.D. Sloley and J.S. Richardson. Brain benzodiazepine receptors in fathead minnows and the behavioral response to alarm pheromone. Pharmacol. Biochem. Behav. 33 435-442, 1989. 

Gee, K. W., Yamamura, H. I. A novel pyrazoloquinoline that interacts with brain benzodiazepine receptors characterization of some in vitro and in vivo properties of CGS 9896. Life Sci. 1982, 30, 2245—2252. 

Braestrup C, Nielsen M, Olsen CE. Urinary and brain p-carboline-3-carboxylates as potent inhibitors of brain benzodiazepine receptors. Proc Natl Acad Sci U S A 1980 121 2288-2292. 

Mennini, T. Cotecchia, S. 8c Garattini, S. 1982. Does ethyl-/ -carboline-3-carboxylate interact with mouse brain benzodiazepine receptors in vivo Journal of Pharmacy and Pharmacology Vol. 34 394-395. 

Bergendorff, O., K. Dekermendjian, M. Nielsen, et al. 1997. Furanocoumarins with affinity to brain benzodiazepine receptors in vitro. Pht/tochemistn/ 44(6) 1121-1124. 

Dekermendjian,K.,J. Ai,M. Nielsen, et al. 1996. Characterisation of the furanocoumarin phellopterin as a rat brain benzodiazepine receptor partial agonist in vitro. Neurosci. Lett. 219 (3) 151-154. 

A medication that causes induction of sleep. The majority of currently available hypnotics (for example benzodiazepine receptor agonists) act via potentiating the brain s inhibitory GABAergic systems, in turn reducing the activity of arousal (i.e. wake promoting) neurotransmitter systems. 

Reynaud M, Petit G, Potard D, et al Six deaths linked to concomitant use of buprenor-phine and benzodiazepines. Addiction 93 1383-1392, 1998 Richards JG, Martin JR Binding profiles and physical dependence liabilities of selected benzodiazepine receptor ligands. Brain Res Bull 43 381-387, 1998... 

Malizia, AL, Cunningham, VJ, Bell, CJ, Liddle, PF, Jones, T and Nutt, DJ (1998) Decreased brain GABA(A)-benzodiazepine receptor binding in panic disorder preliminary results from a quantitative PET study. Arch. Gen. Psychiatry 55 715-720. 

Compounds 227 and 232 were tested in vitro for inhibition of [3H]-diazepam-specific binding to benzodiazepine receptors in membranes from synaptosomes of rat brain and in vivo for their effects on conditioned behavior in rats (89FES29). 

Zanoli P, Giacobazzi A, Vaccari G, Zeneroli ML, Baraldi M Up-regulation of peripheral benzodiazepine receptors in brain areas of rats with galactosamine-induced hepatic encephalopathy in Bengtsson F, Jeppson B (eds) Progress in Hepatic Encephalopathy. Miami, CRC Press, 1991, pp 161-168. 

Lavoie J, Pomier Layrargues G, Butterworth RF Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 1990 11 874-882. 

Yurdaydin C, Walsh TJ, Howard DE, Ha J, Li Y, Jones EA, Basile AS Gut bacteria provide precursors of benzodiazepine receptor ligands in a rat model of hepatic encephalopathy. Brain Res 1995 679 42-48. 

Ducis I, Norenberg L-OB, Norenberg MD. 1990. Effect of phenol and sodium octanoate on the astrocyte benzodiazepine receptor. Brain Res 514 349-351. 

GABAA benzodiazepine j8-carbolines act as inverse agonists of the GABAA benzodiazepine receptor (Mehta and Ticku 1989). Whereas benzodiazepines such as diazepam stimulate Cl- influx, j8-carbolines inhibit it. Harmine, harmaline, harmane, and harmalol inhibit flunitrazepam binding in the micromolar range (half-maximal inhibition between 28 and 130 pM) (Mousah et al. 1986). Endogenous j8-carbolines, such as harmane, have also been found in the human brain, but their endogenous functions are uncertain (Tse et al. 

Montpied P, Martin BM, Cottingham SL, Stubblefield BK, Ginns El, Paul SM. 1988. Regional distribution of the GABA /benzodiazepine receptor (a subunit) mRNA in rat brain. J Neurochem 51 1651-1654. 

Substances with a neuromodulatory effect on brain neurotransmitters by direct actions of specific receptors that modify the actions of the transmitters listed include prostaglandins, adenosine, enkephalins, substance P, cholecystokinin, endorphins, endogenous benzodiazepine receptor ligands, and possibly histamine. CNS, central nervous system. NMDA, N-methyl-D-aspartate. Strych, strychnine. 

The relative contribution of the active metabolites of the benzodiazepines to the overall therapeutic effect of the parent compound will depend on the concentration of the metabolite formed, its agonist potency at central benzodiazepine receptors and its lipophilicity. For example, after the chronic administration of diazepam, desmethyldiazepam accumulates in the brain. As this metabolite has potency at the benzodiazepine receptors equal to diazepam, the metabolite probably plays an important part in the overall action of diazepam. In the case of clobazam, however, even though the active metabolite desmethylclobazam is present in higher concentrations than the parent compound after chronic administration, it has a lower potency than clobazam and therefore is of less importance than the parent compound with regard to the anxiolytic effect. 

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