Biomedical subjects
Publications and source records attributed to C Martini.
Some 3-amino- and 3-hydroxy-8-halosubstituted 6H-indolo[2,3-b] [1,8]naphthyridines were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. All prepared compounds were more active than the corresponding 8-unsubstituted derivatives. Moreover, among these compounds the 8-chloroindolonaphthyridines were clearly the most potent.
Several N-(indol-3-ylglyoxylyl)amino acid derivatives were synthesized and tested for their affinity for the benzodiazepine receptor in bovine cortical membranes. From these compounds, the N-[(5-chloro-, 5-bromo-, or 5-nitroindol-3-yl)glyoxylyl]glycine or -alanine esters were clearly the most potent, while the 5-methoxy analogues were considerably less active. Moreover, esters were more active than the corresponding acids. It is concluded that the affinity of these derivatives for the benzodiazepine receptor is profoundly dependent on amino acid molecular size, as well as the hydrophobic and electronic properties of the compounds.
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In adult cats, local injection of kainic acid (KA) in the inferior olive (IO) of one side, from which the crossed olivocerebellar projection originates, produced asymmetric postural and motor deficits, attributed to selective damage of the olivary neurons. Since aspartate is one of the putative transmitters of the olivocerebellar fibers, experiments were performed to find out whether 6-8 days after injection of KA within the IO of one side produced changes in aspartate receptors binding in different zones of the cerebellar cortex. In particular, binding in the contralateral zones of the cerebellar cortex was referred to proteins contained in membrane suspensions and compared with the control values obtained in the same experiments from the ipsilateral zones. Binding of L-[3H] aspartate decreased on the average to 53.4% of the control value in the medial zone and to 86.1% of the control value in the intermediate and lateral zones of the cerebellar cortex. This reduction varied in different experiments according to the side of the injection, in agreement with the well known pattern of regional distribution of the olivocerebellar projection within the cerebellar cortex. These findings favour aspartate as the putative neurotransmitter of the climbing fibers. The demonstration that binding of aspartate decreased in the cerebellar cortex of one side, 6-8 days after injection of KA in the corresponding IO, indicates that plastic events occur at this level following destruction of the olivocerebellar pathway. In particular, the reduced binding can be attributed either to a decrease in number of the postsynaptic receptor sites for aspartate or to a decreased affinity of this amino acid for the corresponding receptors. These findings, however, do not exclude that an hypersensitivity by denervation may occur at the level of individual Purkinje cells when they are deprived of the climbing fibers input. In order to answer this question further experiments are required to find out how the binding for aspartate is modified at increasing time intervals after the olivary lesion.
The syntheses of some 2-aryl-3-methyl-4,5-dihydro-2H-pyrazolo [4,3-c] quinolin-4-ones and 1-aryl-3-methyl-4,5-dihydro-1H-pyrazolo-[4,5-c] quinolin-4-ones are reported. Some of the latter have shown a high activity in displacing specific [3H]-flunitrazepam binding from bovine brain membranes.
Plasma exchange can induce changes in the biological systems of coagulation, fibrinolysis, complement and kinins, either by contact activation or plasma substitution. In order to know which of the two is responsible, the actual initial and final values and theoretical calculated final values were compared. Fibrinogen, Antithrombin III and platelets fell more than expected, and there was a significant increase in Platelet-Factor four and Betathromboglobulin which was greater than would produced by plasma substitution alone. Fibrinolysis is shortened and white cells rise. Complement and kinins were not significantly changed. During plasma exchange, contact activation actually triggers coagulo-fibrinolytic pathway and stresses cellular components.
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The high-affinity binding site for [3H]Ro 5-4864 has been solubilized from rat kidney using 1% Triton X-100. After lowering the concentration of detergent and using a poly(ethylene glycol) gamma-globulin assay, it has been possible to demonstrate solubilization of about 90% of the binding sites. A single soluble class of binding sites with a Kd of 1.8 nM is found. The order of potency of benzodiazepines is identical for the solubilized receptor and the membrane-bound form. Gel filtration revealed a major peak of binding activity with apparent molecular weight of 215000 and a Stokes' radius of 5.03 nm.
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The presence of a [3H]muscimol binding site on the purified benzodiazepine receptor was demonstrated. The purified protein was apparently homogeneous as shown by sodium dodecyl sulfate polyacrylamide gel electrophoresis (stained with silver), with a molecular weight of 60,000 +/- 3000. The benzodiazepine binding sites were characterized as being of the central type and the [3H]flunitrazepam binding was enhanced by GABA. This activation was antagonized by bicuculline. [3H]Muscimol specifically binds to the benzodiazepine receptor. The Scatchard plot indicates a Kd of 23 nM and the ratio [3H]flunitrazepam/[3H]muscimol is approximately unity.
The activation of the coagulation system--commonly occurring in other extracorporeal circulation--is still debated, in plasma exchange (PE), data being conflicting due to the different types of replacement fluid used in 25 patients treated by PE using a discontinuous plasma separator (14 with freshly-frozen plasma, 8 with half plasma half 5% albumin, 3 with only 5% albumin). The occurrence of leukocytes stress is proved by their marked increase at the end of the procedure while the platelet fall is superimposable to the HTC fall. A coagulation-fibrinolytic activation seems to be demonstrated by plasma increase in endoplatelet constituents, fibrinogen and antithrombin III consumption, and shortening in fibrinolytic tests, but caution must be made in interpreting these results because the donor's plasma units show high levels of platelet endogranular constituents and a wide variable range of coagulation-related proteins, which can interfere with an appropriate evaluation of the results.
The benzodiazepine receptors of bovine brain membranes have been identified by the specific binding of radiolabeled [3H]diazepam. Pretreatment of membranes with N-ethylmaleimide causes a dose- and time-dependent decrease of 45 to 60% in the number of binding sites. No decrease occurs when membranes are pretreated with N-ethylmaleimide before administration, or in the presence, of diazepam. Binding of [3H]diazepam to the remaining sites occurs with the same characteristics as binding to the untreated receptor population.
The benzodiazepine receptor from rat brain was solubilised and purified 5200-fold by affinity chromatography. The affinity column contained an immobilized benzodiazepine (delorazepam) and biospecific elution with 6 mM-chlorazepate was achieved. The purified receptor is apparently homogeneous in SDS-polyacrylamide gel electrophoresis. The native protein had a molecular weight of 240,000, and the subunit one of 60,000. The dissociation constant (KD) is 8 nM for [3H]diazepam. A correlation exists between the value of affinity obtained for benzodiazepine derivatives and their known pharmacological effectiveness.
The reactivity of some 6H-indolo[2,3-b] [1,8]naphthyridines (II) and 11H-indolo[3,2-c] [1,8]naphthyridines (III) in displacing specific [3H] diazepam binding from bovine brain membranes was examined. All the indolonaphthyridines tested are active and show a higher activity than indole and tryptophan. The inhibition is due to direct interaction with the benzodiazepine binding sites. Some structure-activity relationships are discussed.
The use of affinity chromatography as means of isolating/purifying proteins which have an affinity for benzodiazepine is described. Three such drugs are employed: chlorazepate, clonazepam and delorazepam. The results presented in this paper indicate that the proposed technique only works for chlorazepate and delorazepam. In fact these benzodiazepine-Sepharose derivatives are able to retain specifically proteins from human serum and rat kidney, lung, skeletal muscle and brain.
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