Benzodiazepines endogenous

Ammonia Bacterial flora Benzodiazepines, endogenous Encephalopathy, hepatic Liver cirrhosis Rifaximin... 

Several methods are being studied to enhance the stabiUty of peptide mimics and improve their stereochemical similarity to the endogenous peptides. For example, the tetrapeptide Cys—Val—Phe—Met, a potent inhibitor of Ras famesyltransferase, is proposed to exist in a turned conformation, which mimics the endogenous peptide during enzyme binding. This conformation is successhiUy mimicked by 3-amino-l-carboxymethyl-5-phenyl-benzodiazepin-2-onederivatives (198) (142). 

THE QUEST FOR THE ENDOGENOUS BENZODIAZEPINE RECEPTOR LIGAND ( ENDOZEPINES )... 

Table 19.4 Putative endogenous ligands for the benzodiazepine binding domain on the GABAa receptor...

Although, by analogy with the opioids, one would expect there to be an endogenous ligand for the widely distributed benzodiazepine receptor, its existence remains uncertain and we must be alert to the possibility that any such ligand(s) could have either agonist or inverse agonist activity. 

The undisputed efficacy of benzodiazepines in relief of anxiety led to the question of whether this disorder could arise from abnormal concentrations in the brain of an endogenous ligand or a malfunction of the benzodiazepine/GABA receptor system. An important study, aimed at distinguishing between these possibilities, has been carried out in humans (Nutt et al. 1990) and was based on the premise that anxiety could be caused by either ... 

Inadequate activity of an endogenous ligand which is a benzodiazepine receptor agonist and suppresses anxiety. In this case, the administration of the antagonist, fiumazenil, should induce anxiety in normal subjects and exacerbate anxiety in anxious patients. 

De Robertis, E, Pena, C, Paladini, AC and Medina, JH (1988) New developments on the search for endogenous ligand(s) of central benzodiazepine receptors. Neurochem. Int. 13 1-11. 

False neurotransmitters resulting from increased levels of aromatic amino acids, high levels of y-aminobutyric acid, and endogenous benzodiazepines have also been implicated in HE. These substances bind to both the y-aminobutyric acid and benzodiazepine receptors and act as agonists at the active receptor sites.20... 

Avallone R, Zeneroli ML, Venturini I, Corsi L, Schreier P, Kleinschnitz M, Ferrarese C, Farina F, Baraldi C, Pecora N, Frigo M, Baraldi M Endogenous benzodiazepine-like compounds and diazepam binding inhibitor in serum of liver cirrhosis patients with and without encephalopathy. Gut 1998 42 860-867. 

Basile AS, Gammal SH, Jones EA, Skolnick P GABA-A receptor complex in an experimental model of hepatic encephalopathy Evidence for elevated levels of an endogenous benzodiazepine receptor complex ligand. J Neurochem 1989 53 1057-1063. 

De Bias AL, Park D, Friedrich P Endogenous benzodiazepine-like molecules in human, rat and bovine brains studied with a monoclonal antibody to benzodiazepines. Brain Res 1987 413 275-284. 

Olasmaa M, Rothstein JD, Guidotti A, Weber PJ, Paul SM, Spector S, Zeneroli ML, Baraldi M, Costa E Endogenous benzodiazepine in human and animal hepatic encephalopathy. J Neurochem 1990 55 2015-2023. 

The GABA-gated chloride ion channel is modulated by several classes of drugs that bind to allosteric sites on the receptor complex the benzodiazepines, barbiturates and related intravenous general anesthetics such as etomidate and propofol, as well as anesthetic steroids and endogenous neurosteroids. It appears that some types of GABAa receptor are directly enhanced by ethanol and volatile general anesthetics (Fig. 16-2) [7,8,20]. 

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. 

Rommelspacher H, Nanz C, Borbe HO, Fehske KJ, Muller WE, Wollert U. (1980). 1-Methyl-beta-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding. Naunyn Schmiedebergs Arch Pharmacol. 314(1) 97-100. 

It is of historical interest to note that the disclosure of U-50488 occurred at roughly the same time as two chemically unrelated compounds which behave as poorly selective kappa agonist analgesics. These are the benzodiazepine, tifluadom (6) [17] and the amino-terminal nonapeptide fragment of dynorphin, Dyn (1-9), (7) (kappa A) = 0.21 nM, mu K = 3.6 nM delta K, = 3.2 nM) [18], which is thought to be the endogenous kappa opioid agonist. 

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. 

Other than adenosine, there are several peptides which induce sleep (e.g., delta sleep inducing peptide). Together with endogenous chemicals interacting with the GABA benzodiazepine receptor site (e.g., (3-carbolines) identified in... 

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