�ber die Eiwei�bindung von Bisguanylhydrazonen

BENZODIAZEPINE RECEPTOR BINDING IN RAT BRAIN AND RAT SPINAL CORD MEMBRANES

Die Affinit�t von 3,3?-Dimethyl-4,4?-diacetyl-diphenyl-bisguanylhydrazon zu verschiedenen Organen des Meerschweinchens

�ber die Herzglykosid-artige Wirkung von Progesteronbisguanylhydrazon (Progesteronbiguazon)

Die Wirkungen von Progesteronbisguanylhydrazon, g-Strophanthin und Digitoxigenin werden mit folgenden Methoden verglichen: Isolierte Vorhofe von Meerschweinchen, Ratten, Kaninchen und jungen Katzen; Herz-Lungen-Praparat des Meerschweinchens; cellulare Membran- und Aktionspotentiale von Vorhofmuskulatur; Natrium- und Kalium-Bestimmungen und Messung des Calcium-Umsatzes in isolierten Vorhofen von Meerschweinchen; isolierte Darmpraparate von Kaninchen und Meerschweinchen; Messung des Kalium-Gehaltes von „Kalteerythrocyten“ von Meerschweinchen, Kaninchen und Menschen. Ferner wird das Vergiftungsbild von Progesteronbisguanylhydrazon an der Maus beschrieben und gepruft, ob Cortisonbisguanylhydraz…

Über eine mangelnde Parallelität zwischen Ionenpumpenhemmung und Kontraktionskraftsteigerung

Δ 5-Pregnen-3,20-dione-N,N'-ethylpyrrolidine-bisguanylhydrazone and Δ5-pregnen-3β-hydroxy-20-one-N,N'-ethyl-pyrrolidine-monoguanylhydrazone inhibit the activity of the ionic pump of cold-stored erythrocytes of guinea-pigs. The contractile force of isolated guinea-pig auricles is decreased by the mono-derivate and increased by the bis-derivate in spite of the similar action upon the pumping mechanism.

?-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…

Circular dichroism studies on the interaction of sulfonylureas with insulin

The interaction of 5 sulfonylurea derivatives with insuline was investigated by means of circular dichroism measurements. It was found that all sulfonylureas investigated decrease the ellipticity band of insulin at 208 nm, whereas the band at 222 nm remains unaffected. It is suggested that these observations are due to a change of the insulin conformation, provoked by the interaction of the drugs with insulin. It is assumed that such an effect on the insulin conformation can influence the binding properties of insulin, e.g. in respect to the insulin aggregation, to the binding to insulin antibodies and to a bound, inactive form of insulin in the plasma. Some other drugs have similar, but mo…

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…

Über die Wirkung einfacher Bisguanylhydrazone auf Herzgewebe

Interactions of benzodiazepines with human serum albumin. Circular dichroism studies.

The circular dichroism spectra of 12 benzodiazepine derivatives studied in presence of human serum albumin are presented. Nearly all substances give biphasic extrinsic Cotton effects. At the CD maxima the molar ellipticities and the anisotropy factors are calculated. The influence of the chemical structure of the benzodiazepines on the induced Cotton effect is discussed. There is a linear correlation between the anisotropy factors and the logarithms of the partition coefficients of the substances. It is suggested that the phenyl ring of the benzodiazepine molecule is one of the essential groups for the binding of these substances to human serum albumin.

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.

Das Verhalten des cellul�ren Calciums unter Depolarisation mit Kalium am Herzmuskel von Meerschweinchen

Benzodiazepines: specific competitors for the binding of L-tryptophan to human serum albumin.

By means of the gel filtration technique, the effect of nine benzo-diazepine derivates on the binding of l-tryptophan to human serum albumin was investigated. Using equimolar tryptophan and benzodiazepine concentrations, all benzodiazepines with binding constants higher than 104 (M−1), displace l-tryptophan from its binding site to a high degree. The mechanism of the displacement was characterized as a competition for a common binding site. Some of the benzodiazepines displace l-tryptophan to a greater extent than salicylic acid. The benzodiazepines and tryptophan are the only substances known with a high degree of stereospecific binding to human serum albumin. This study shows that there i…

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…

Characterization of the binding of benzodiazepines to human serum albumin

The binding of eleven benzodiazepine derivatives to human serum albumin (HSA) was determined by means of sephadex gel filtration. The albumin binding of the substances was characterized by the percentage of bound drug, the binding constants k +, K 1 and m, the number of binding sites per albumin molecule, and the free binding energy. Under the conditions chosen in these experiments there seems to exist only one binding site of the same type for all investigated benzodiazepines at the HSA molecule. The affinities of the benzodiazepines to this binding site are very different. It is discussed which part of the benzodiazepine molecule represents the main binding group.

�ber einen Unterschied in der Art der Herzwirksamkeit von Mono- und Bisguanylhydrazonen

Die Verteilung von Progesteron- und Dodecandion-2,11-bisguanylhydrazon im Meerschweinchenorganismus

Regional distribution of high-affinity L-tryptophan uptake in rat brain

Abstract L-tryptophan is accumulated by slices of seven regions of the rat brain in a saturable, energy-depending fashion, with K m -values ranging from 53 to 142 μM. The maximal number of L-tryptophan accumulating sites differs only by about two-fold for the brain regions investigated. The regional distribution of the high-affinity L-tryptophan uptake does not correlate with the amount of serotonin synaptosomal uptake and apparent receptor binding. It is assumed that a specific role of the L-tryptophan uptake system within the serotoninergic system in the brain is questionable.

�ber die Wirkung einiger herzwirksamer Bisguanylhydrazone auf den Veratrineffekt am Frosch-Sartoriusmuskel

Die Wirkung einiger Guanylhydrazone sowie von Tyramin auf die „Veratrine-Response“ des Froschsartoriusmuskels wurden untersucht. Von den drei „herzglykosidartigen“ Bisguanylhydrazonen zeigten BG 60 und BG 31 den unspezifischen Veratrinantagonismus des Chinidins. BG 85 hingegen beeinfluste die VR „herzglykosidartig“. Von den drei „tyraminartigen“ Substanzen BG 81, MG 41 und Tyramin wirkten die letzten zwei „chinidinartig“, wahrend BG 81 trotz seiner „tyraminartigen“ Wirkung die VR „herzglykosidartig“ beeinfluste.

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…

�ber die Eiwei�bindung von Bisguanylhydrazonen der 4,4'-Diacetyl-diphenyl-Reihe in Abh�ngigkeit von der Struktur

�ber die intracellul�re Verteilung eines aliphatischen und aromatischen Bisguanylhydrazons im Meerschweinchenherzen

Influence of pH on the benzodiazepine-human serum albumin complex. Circular dichroism studies.

The influence of pH on the binding of benzodiazepine derivatives to HSA was studied by circular dichroism measurements and by gel filtration. The binding of nearly all benzodiazepines is increased by rising the pH from 6.60 to 8.20. For flurazepam, clonazepam, and nitrazepam this increase in binding is due to an increase of the affinities, while for the other substances the affinity remains constant and the number of binding sites is increased from one to two. The changes in binding of the benzodiazepines by rising the pH are explained by a cationic amino acid residue near or at the benzodiazepine binding site of the HSA molecule. This second binding site is not detectable by circular dichr…