�ber die Bedeutung der Plasmaproteinbindung f�r Verteilung und Wirkung von Tranquillantien vom Benzodiazepintyp

This paper discusses the problem if the plasma protein binding of benzodiazepine derivatives can influence distribution and pharmacological activity of the drugs. The distribution of the benzodiazepines in the organism is influenced not only by the plasma protein binding of the drugs, but also by several other factors, especially since the drugs are mostly lipophilic. Thus, an effect of the plasma protein binding on the distribution can only be expected if the benzodiazepine derivative is highly bound to the plasma proteins. Thus results have been shown only for diazepam and chlordiazepoxid, which indicate an effect of the plasma protein binding on distribution and pharmacological activity,…

Characterization of a common binding site for basic drugs on human ?2-acid glycoprotein (orosomucoid)

The interaction of chlorpromazine, dl-propranolol, and imipramine with isolated α1-acid glycoprotein is characterized by relatively high association constants and only one binding site per protein molecule. The mutual displacement between the three drugs indicates that all three compounds are bound to the same binding site. Several other basic drugs from different pharmacological and chemical classes also displace chlorpromazine, dl-propranolol, and imipramine with potencies, one would predict from their association constants or from the degree of their plasma binding in humans. It is concluded that displacement phenomena like those observed in this study in vitro are likely to occur also i…

Peripheral benzodiazepine binding sites on striated muscles of the rat: Properties and effect of denervation

In order to test the hypothesis that peripheral benzodiazepine binding sites mediate some direct effects of benzodiazepines on striated muscles, the properties of specific 3H-Ro 5-4864 binding to rat biceps and rat diaphragm homogenates were investigated. In both tissues a single population of sites was found with a KD value of 3 nmol/l. The density of these sites in both muscles was higher than the density in rat brain, but was considerably lower than in rat kidney. Competition experiments indicate a substrate specificity of specific 3H-Ro 5-4864 binding similar to the properties already demonstrated for the specific binding of this ligand to peripheral benzodiazepine binding sites in many…

?-Carboline binding indicates the presence of benzodiazepine receptor subclasses in the bovine central nervous system

Receptor binding studies were performed with tritiated propyl β-carboline-3-carboxylate ([3H]PrCC), tritiated ethyl β-carboline-3-carboxylate ([3H]ECC), and tritiated flunitrazepam ([3H]FNT) in membrane preparations from different regions of the bovine brain and retina. Specific binding in all regions investigated was associated with benzodiazepine receptor sites. However, not all benzodiazepine receptor sites. However, not all benzodiazepine receptors in the regions investigated as determined by the specific binding of tritiated flunitrazepam ([3H]FNT) are available for [3H]PrCC suggesting that specific [3H]PrCC binding labels only one subclass or subpopulation of the benzodiazepine recept…

1-Methyl-?-carboline (Harmane), a potent endogenous inhibitor of benzodiazepine receptor binding

The interaction of several beta-carbolines with specific [3H]-flunitrazepam binding to benzodiazepine receptors in rat brain membranes was investigated. Out of the investigated compounds, harmane and norharmane were the most potent inhibitors of specific [3H]-flunitrazepam binding, with IC50-values in the micromolar range. All other derivatives, including harmine, harmaline, and several tetrahydroderivatives were at least ten times less potent. Harmane has been previously found in rat brain and human urine, so it is the most potent endogenous inhibitor of specific [3H]-flunitrazepam binding known so far, with a several fold higher affinity for the benzodiazepine receptor than inosine and hy…

The binding of intravenous and oral biliary contrast agents to human and bovine serum albumin

The binding of two homologous series of oral and intravenous biliary contrast agents to human and bovine serum albumin was investigated using the gel filtration technique. All intravenous compounds are bound to human serum albumin via one high affinity and several low affinity binding sites. Within the concentration range investigated, about 3--5 high affinity binding sites for the oral compounds were found on human serum albumin. In general, the intravenous compounds have a greater affinity for human serum albumin than the oral compounds. No significant differences were found for the binding of the oral compounds to human or bovine serum albumin, while the intravenous compounds have a high…

Azapropazone binding to human serum albumin

Azapropazone, a new non-steroidal antiinflammatory drug, is strongly bound to human serum albumin. As revealed by Scatchard analysis, one high-affinity binding site with an association constant of about 1.2 x 10(6)M-1 and two low-affinity binding sites with association constants of about 0.05 x 10(6)M-1 were found. While the high-affinity binding site of azapropazone is clearly not identical with the diazepam or digitoxin binding sites of human serum albumin, contradictory evidence was found by optical measurements and displacement studies for the similarity of the azapropazone and the warfarin binding site of human serum albumin. At present, it is suggested that both drugs bind to differen…

Benzodiazepine receptor binding: the interactions of some non-benzodiazepine drugs with specific [3H] diazepam binding to rat brain synaptosomal membranes.

The interaction of several non-benzodiazepine drugs with [3H] diazepam binding to benzodiazepine receptors in rat brain synaptosomal membranes was investigated. Baclofen, benzoctamine, hydroxyzine, chlorpromazine, haloperidol, imipramine, and amitriptyline displace specific [3H] diazepam binding, but the concentrations needed are too high to explain pharmacological effects of these drugs by an interaction with benzodiazepine receptors. The most potent non-benzodiazepine drug for inhibiting specific [3H] diazepam binding was methaqualone (IC50 value of 150 micrometer). It is suggested that interactions with benzodiazepine receptors may account for the anxiolytic and anticonvulsive side effec…

Inhibition of GABA and benzodiazepine receptor binding by penicillins.

Penicillins are thought to be GABA receptor antagonists. In order to determine the affinities of various penicillin derivatives for the GABA receptor, their potencies as inhibitors of specific [3H]GABA binding to rat brain membranes were investigated. All investigated penicillins inhibit specific [3H]GABA binding, with IC50 values ranging from 2 to 60 mM. The results are consistent with the assumption that penicillins are weak GABA receptor antagonists.

Pharmacological basis of the anxiolytic and antidepressant properties of Silexan®, an essential oil from the flowers of lavender.

Silexan®, a proprietary essential oil manufactured by steam distillation from Lavandula angustifolia flowers showed pronounced anxiolytic effects in patients with subthreshold anxiety disorders and was also efficacious in patients with Generalized Anxiety disorder (GAD). Moreover, evidences for antidepressant-like properties of Silexan® have been observed in anxious patients suffering from comorbid depressive symptoms and in patients with mixed anxiety-depression disorder (ICD-10 F41.2). In accordance with the clinical data Silexan® is active in several behavioral models in rodents at rather low concentrations indicating potent anxiolytic and antidepressive properties. As possible mechanism…

Oligopeptide der β-Carbolin-3-carbonsäure - Synthese und Affinität zu Benzodiazepinrezeptoren

Es wurden Oligopeptide der β-Carbolin-3-carbonsaure dargestellt und deren Affinitat zum Benzodiazepinrezeptor in Mausehirn-Membranen bestimmt. Uber Struktur-Affinitatsbeziehungen wird berichtet. Oligopeptides of β-Carboline-3-carboxylic Acid - Synthesis and Benzodiazepine Receptor Affinity Oligopeptides of β-carboline-3-carboxylic acid were prepared and tested with respect to their affinity for the benzodiazepine receptor in mouse brain membranes. Structure-affinity relationships are reported.

Benzodiazepine receptor interactions may be involved in the neurotoxicity of various penicillin derivatives

The interaction of seven penicillin derivatives with specific [3H]flunitrazepam binding to benzodiazepine receptors was investigated. The affinities of the penicillins for benzodiazepine receptor seemed to depend on the lipophilia of the derivatives. The concentrations of the penicillins which inhibit specific [3H]flunitrazepam binding are consistent with penicillin levels found in the central nervous system of patients developing penicillin induced convulsions. The results suggest that penicillins inhibit GABAergic transmission not only at the GABA receptor, but also at the benzodiazepine receptor, which is thought to be part of a neuronal system facilitating GABAergic transmission. Both m…

Beta-carbolines as benzodiazepine receptor ligands II: Synthesis and benzodiazepine receptor affinity of beta-carboline-3-carboxylic acid amides.

Numerous beta-carboline-3-carboxamides were synthesized by amidation of beta-carboline-3-carboxylic acid, with various amino acids and amino acid esters serving as amine components, and tested in respect to their affinity for the benzodiazepine receptor in mouse brain membranes. The title compounds have affinities in the low micromolar range. The results are discussed with respect to their relevance for a possible beta-carboline structure containing the endogenous ligand of the benzodiazepine receptor.

l-Glutamate receptor binding in bovine retina

Using a centrifugation technique saturable specific [ 3 H]glutamate binding in bovine retina could be demonstrated. Scatchard analysis revealed only one population of binding sites with a dissociation constant of about 3 μ m and a maximal number of binding sites of about 0·2 pmol/mg retinal protein. Several glutamic acid analogues inhibit specific [ 3 H]glutamate binding in bovine retina with half-maximal inhibitory concentrations similar to those reported in other areas of the CNS. Specific [ 3 H]glutamate binding and sodium dependent synaptosomal uptake of glutamate are largely concentrated in the P2 fraction of bovine retina homogenates consisting of conventionally sized synaptosomes. Th…

Olesoxime improves cerebral mitochondrial dysfunction and enhances Aβ levels in preclinical models of Alzheimer's disease.

Abstract Background Approved drugs for Alzheimer's disease (AD) only have a symptomatic effects and do not intervene causally in the course of the disease. Olesoxime (TRO19622) has been tested in AD disease models characterized by improved amyloid precursor protein processing (AβPP) and mitochondrial dysfunction. Methods Three months old Thy-1-AβPPSL (tg) and wild type mice (wt) received TRO19622 (100 mg/kg b.w.) in supplemented food pellets for 15 weeks (tg TRO19622). Mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) levels were determined in dissociated brain cells (DBC). Respiration was analyzed in mitochondria isolated from brain tissue. Citrate synthase (CS) activ…

Psychotropic drug competition for [3H]imipramine binding further indicates the presence of only one high-affinity drug binding site on human α1-acid glycoprotein

Binding of several phenothiazine neuroleptics to a common binding site of alpha 1-acid glycoprotein, orosomucoid.

The interaction of several phenothiazine neuroleptics with alpha 1-acid glycoprotein was investigated using circular dichroism and equilibrium dialysis techniques. For chlorpromazine only, one high-affinity binding site of the protein was found. The binding of the drug to this single site generated typical polyphasic extrinsic Cotton effects. Since several other phenothiazine neuroleptics gave qualitatively comparable extrinsic Cotton effects in the presence of alpha 1-acid glycoprotein and potently inhibited the binding of chlorpromazine to the single site, it was concluded that all phenothiazine derivatives investigated bound preferentially to only one common binding site of the alpha 1-a…

Über den Einfluß von Actinomycin D auf die Acridinfluorescenz von L-Zellen in vitro

L 5178-Y-Zellen wurden bis zu 48 Std mit Actinomycin D (C1) inkubiert und auf ihre Sekundarfluorescenz nach Acridinorange-Fluorochromierung untersucht. Dabei zeigte sich, das vor Actinomycinzugabe nahezu alle Zellen eine kupferrote Fluorescenz in Kern und Cytoplasma aufweisen. Mit zunehmender Inkubationsdauer nimmt der Anteil der rot fluorescierenden Zellen stetig ab, wahrend der der Zellen mit ausschlieslich gruner Sekundarfluorescenz zunimmt. Herauslosen der Ribonucleinsauren durch RNase-Behandlung ruft den gleichen Farbwechsel hervor. Nach 48 Std fluorescieren nahezu alle Zellen grun. Die Anderung des Farbwertes last sich durch Abtoten der Zellen mit Athanol unterbrechen und fixieren.

Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties.

Abstract Background Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. Methods We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through conve…