Pharmacological targeting of glutamate-gated chloride channels (GluCls) is a potent anthelmintic strategy, evidenced by macrocyclic lactones that eliminate numerous roundworm infections by activating roundworm GluCls. Given the recent identification of flatworm GluCls and the urgent need for drugs against schistosomiasis, flatworm GluCls should be evaluated as potential anthelmintic targets. This study sought to identify agonists or modulators of one such GluCl, SmGluCl-2 from the parasitic flatworm Schistosoma mansoni. The effects of nine glutamate-like compounds and three monoterpenoid ion channel modulators were measured by electrophysiology at SmGluCl-2 recombinantly expressed in Xenopus laevis oocytes. For comparison with an established anthelmintic target, experiments were also performed on the AVR-14B GluCl from the parasitic roundworm Haemonchus contortus. l-Glutamate was the most potent agonist at both GluCls, but l-2-aminoadipate, d-glutamate and d-2-aminoadipate activated SmGluCl-2 (EC50 1.0 ± 0.1 mM, 2.4 ± 0.4 mM, 3.6 ± 0.7 mM, respectively) more potently than AVR-14B. Quisqualate activated only SmGluCl-2 whereas l-aspartate activated only AVR-14B GluCls. Regarding the monoterpenoids, both GluCls were inhibited by propofol, thymol and menthol, SmGluCl-2 most potently by thymol (IC50 484 ± 85 μM) and least potently by menthol (IC50 > 3 mM). Computational docking suggested that agonist and inhibitor potency is attributable to particular interactions with extracellular or membrane-spanning amino acid residues. These results reveal that flatworm GluCls are pharmacologically susceptible to numerous agonists and modulators and indicate that changes to the glutamate γ-carboxyl or to the propofol 6-isopropyl group can alter the differential pharmacology at flatworm and roundworm GluCls. This should inform the development of more potent compounds and in turn lead to novel anthelmintics.

The oxidation of the (E)- and (Z)-N-propenylbenzamides (1) by dimethyldioxirane (DMD) in acetone solution leads to the alpha-amido epoxides 2, which were detected by low-temperature NMR spectroscopy, above -50 degrees C they dimerize to the diastereomeric dioxanes 3, in the presence of methanol they are trapped to form the hemiaminal 4, while mCPBA cleaves them to N-formylbenzamide and acetaldehyde.

Novel lipophilic γ-amino acids 8 and 9 analogous to GABA containing cyclopropane rings are synthesized by Rh(II)-catalyzed reaction of diazo compounds 2 and 3 with N,N-bis(trimethylsilyl)allylamine (1) and subsequent hydrolysis. In addition, routes are described leading to the vinylogous GABA analogue 15 and to the unusual tricyclic γ-amino acid 20.

1,2-Oxazine 1 ws converted into an unusual condensation product 5 by treatment with tetra-n-butylammonium fluoride. the hydrogenolysis of 1 with Pd/C as catalyst provided the expected primary amine 9, whereas the same reaction with the ethoxycarbonyl-substituted 1,2-oxazine 2 as starting material gave the 4-methylproline derivative 10 after N-protection. Deprotonation at C-4 of 1 required rather harsh conditions but cleanly afforded the corresponding lithiated intermediate 11. Treatment of 11 with electrophiles provided the C-4-substituted derivatives 12-16 in good to moderate yield, but generally with very high diastereoselectivity. The overall substitution process preferentially occurs with retention of configuration which is explained by assuming ion pair structure B for intermediate 11.

5,6-Dihydro-4H-1,2-oxazines 1a-b, 2, and 3 are easily brominated at C-4 with N-bromosuccinimide/dibenzoyl peroxide in tetrachloromethane. The bromo substituent is incorporated with surprisingly high diastereoselectivity trans to the substituent dt C-6.4-Bromo-5,6-dihydro-4H-1,2-oxazines are useful reagents for substitution reactions with N-nucleophiles such as primary amines and azide ions. Inversion of configuration at C-4 provides derivatives of 4-amino-1,2-oxazines with uniform relative configuration. As a minor byproduct the dibromo adduct 7 is obtained by bromination of 3. The dehydrohalogenation of this compound allows the synthesis of the 4-bromo-6H-1,2-oxazine 12. The presented reaction sequence thus constitutes an 'umpolung'' reaction that allows the introduction of nucleophiles into a position of the oxazine ring that so far was accessible only for electrophiles. The diastereoselectivity of the bromination reaction is discussed.

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NN-Bis(trimethylsilyl)-2-propynylamine (1) was smoothly transformed into alkyl 2-cyclopropenecarboxylates 2 and 3 by alkyl diazoacetates under rhodium(II) acetate dimer catalysis. The corresponding gamma-amino acid 7 (2-aminomethyl-2-cyclopropene-carboxylic acid) was prepared in good yield from 3 via 5 and 6 by desilylation, ester cleavage under acidic conditions, and neutralization. Diels-Alder reaction of cyclopropene derivative 2 with cyclopentadiene selectively provided methyl 2-[bis(trimethylsilyl)aminomethyl]tricyclo[3.2.1.0(2,4)]oct-6-ene-3-carboxylate (8).

N-Silylated allylamines 1 are effectively transformed into methyl cyclopropanecarboxylates 2 by methyl diazoacetate under Rh2(OAc)4 catalysis. Derivatives 2a and 2b are smoothly converted into trans-substituted amino acids 6a and 6b, respectively, and to bicyclic gamma-lactams 5a and 5b. The pharmacologically interesting gamma-aminobutyric acid (GABA) analogue trans-6a is now available in few steps. Photochemical and thermal Fe(CO)5-induced hydrogen shift converts allyamine derivatives 1 into N-silylated enamines 7. While enamine (E)-7a can be cyclopropanated with methyl diazoacetate under Cu(acac)2 catalysis to afford the desired cyclopropane derivatives 8a in good yield, the other enamines are rather unreactive towards the carbenoid. Use of an optically active catalyst provides 8a with an ee of 56% (cis) and 20% (trans). Acid-induced ring cleavage of 8a gives the beta-formyl ester 10a, and reduction of 8a followed by desilylation provides the amino-cyclopropane 14 in good overall yield, thus demonstrating that cyclopropanes like 8a can serve as useful synthetic intermediates.

Esophageal autopsy specimens from 11 subjects were used to determine observer variation and sampling error in assessing alterations attributed to gastroesophageal reflux. Inter- and intraobserver variation exceeded 20% even when the diagnosis was limited to a normal and abnormal reading. Marked differences in basal cell thickness but not in papillary height occurred when specimens were obtained from different levels of the lower esophagus. The differences were less marked in specimens obtained from the same level. Based on these data the reliability of basal cell thickness and papillary height as an index of gastroesophageal reflux appears limited.

When compared with results from humid fibers, characteristic changes of the SAXS-pattern taken from dried collagen fibers have been observed. The average lateral width of the various reflexions increases with the order of reflexion whereby a fluctuation is superimposed, the type of which cannot easily be related to the reflexion order. Moreover, each of the reflexions is obviously laterally split into three components. An explanation of these characteristics can be given with the aid of a distinct model, assuming that the collagen fibrils have definitely varying diameters along their axis, whereby paracrystalline distortions appear, represented by nematic fluctuations. Additionally, there is a need for postulating a shear deformation of parts of the sample.

It is shown that there exists a direct correlation between the light diffraction pattern of an electron-microscopical picture and the X-ray small angle scattering. By this means it can be proved for native collagen prepared by a special method that the density pattern of stained samples imaged in the electron microscopy is identical with the density pattern available from moist fibres. The reflex intensities of the small angle X-ray scattering are taken for calculating the density structure whereby the necessary phases are delivered by the electron microscopic examination combined with light diffraction.

Either porous polyester-polyurethane cylindrical sponges with a diameter of 12 mm (thickness 6 mm) or rectangular sponges (dimensions 120 × 20 × 5 mm) were implanted paravertebrally in the subcutis of a total of 118 rats of different ages (1–15½ months). It was established that the rate of tumor formation increased with the size of the implant from 12.2% (cylindrical sponges) to 26.6% (rectangular sponges). Furthermore it could be shown that in animal experiments it is the age of the rats that plays the decisive role in sarcogenesis and not the latend period (time from the implantation until development of the tumor), in that young animals first develop malignant mesenchymal tumors after a mean 17.2 months whereas in old rats these had already developed after 6.3 months.

UNLABELLED Former investigations (Rakow et al., 1970, 1971a, b 1974) have demonstrated a constancy of the adipocyte number in white adipose tissue (parepididymal fat pads) of lean NMRI-albino-mice and aurothioglucose-obese NMRI-albino-mice during starvation and subsequent refeeding. In contrast the number of cells of connective tissue showed great variations under the experimental conditions mentioned above. The present paper describes which changes of the different cell populations within the adipose tissue could be demonstrated in lean and obese C57BL/6 J-mice. MATERIAL AND METHODS The investigations were performed with obese and lean male C57BL/6 J-mice. The control animal groups were fed for six weeks 2.5 g (lean mice) and 2 g (obese mice), respectively, Altromin 1115R daily (starvation phase). After this time some of these animalwere killed (exp. groups H). The remaining animals now were fed Altromin 1115R and additional oat falkes ad libitum. Three (exp. groups HW3) and seven (exp. groups HW 7) days, respectively, after the beginning of the refeeding phase the animals were killed. After sacrifice the epididymal fat pads were weighed and treated with either (fat extraction). The dry mass was hydrolized with PCA (0.5 m, 90 degrees C, 40 min). In the supernatant the DNA (Burton, 1956), RNA (Ceriotti, 1955) and polysaccharide content (Seifter et al., 1950) were measured. The sediment was hydrolized with NaOH (0.5 n, 37 degrees C, 24 hrs). In this solution the protein content (Lowry et al., 1951) was determined. In addition fat cells were isolated according to Rodbell (1964). The fat cell diameters were determined microscopically and the average masses of the fat cells were estimated. From the wet weight of the fat pads and the average fat cell mass and number of fat cells were calculated. The remaining suspension of fat cells and cells of connective tissue were utilized for cell smears. These cell smears were stained with Schiff's reagent (Feulgen et al., 1924; Graumann, 1953). With an integrating microdensitometer (Deeley, 1955) the average relative DNA-content of single cell nuclei was measured and the ploidy patterns were estimated. The DNA-content was measured chemically according to Burton (1956). From the whole DNA-content of the fat pads and the DNA-content of the fat cell population the number of cells of the connective tissue was calculated...

Um einen Einblick in die Reaktion der Fettzell- und der Gefäßbindegewebszellpo-pulation des weißen Fettgewebes (parepididymaler Fettkörper) unter verschiedenen Ernährungsbedingungen zu erhalten, wurden normalgewichtige und fettsüchtige C 57 BL/6 J-Mäuse einer chronischen Mangelernährung unterzogen und anschließend wieder aufgefüttert. Methodisch wurden gleichzeitig chemische Bestimmungen (DNS: Ermittlung der Gesamtzellzahl), Bestimmungen des Fettzelldurchmessers (Berechnung der Fettzellzahl) und zytophotometrische Messungen (Ermittlung des DNS-Gehaltes der einzelnen Zelle und der Ploidieklassen der Zellpopulation) durchgeführt.

UNLABELLED Former investigations (Rakow et al., 1970, 1971 b) on epididymal fat pads of lean NMRI-Albino-mice during starvation and refeeding have shown that the number of fat cells (adipocytes) remained unchanged while the number of cells o connective tissue decreased during starvation and increased during the refeeding period. In the present paper the problem has been investigated whether these variations could be demonstrated also in NMRI-albino-mice obesified by administration of aurothioglucose. MATERIAL AND METHODS The investigations were performed with male NMRI-Albino-mice rendered obese by administration of aurothioglucose (800 mg per kg body weight). These animals were fed 2.5 g Altromin 1115 R daily for six weeks. After this they were fed Altromin 1115 R and additional oat flakes ad libitum for three (exp. groups HW3) and seven (exp. groups HW 7) days respectively. After this time the animals were sacrificed. The epididymal fat pads were removed and weighed. One of both pads of each animal was used for chemical investigations. After PCA-treatment (0.5 n, 90 degrees C. 15 min.) the DNA (Burton, 1956) and RNA (Ceriotti, 1955) was determined in the supernatant. After NaOH-treatment (0.5 n, 37 degrees C, 24 Hrs) the noncollagen protein content (Lowry et al., 1951) of the sediment was estimated. After HCl-treatment (25%, 110 degrees C, 20 hrs.) the collagen content (Stegemenn, 1958; modified by Rauskolb, 1967) was determined. The remaining fat pad was used for calculations of cell numbers in the fat cell and connective tissue cell compartment. For this reason fat cells were isolated according to Rodbell (1964). The fat cell diameters were determined microscopically and the average masses of the fat cells were estimated. From the wet weight of the fat pads and the average fat cell mass the number of fat cells was calculated. The remaining suspension of fat cells and cells of connective tissue was utilized for cell smears. These smears were stained with Schiff's reagent (Feulgen et al., 1924; Graumann, 1952). With an integrating microdensitometer (Deeley, 1955) the average relative DNA-content of single cell nuclei were measured and the ploidy patterns were estimated. From the whole DNA-content of the fat pads and the DNA-content of the fat cell population the number of cells of the connective tissue was calculated...

Um einen Einblick in zahlenmäßige Veränderungen des Fettzell- und Nichtfettzell-kompartimentes der epididymalen Fettkörper (weißes Fettgewebe) von experimentell ausgelöst (Aurothioglukose) fettsüchtigen Mäusen (NMRI) im chronischen Hunger und bei Wiederauffütterung zu gewinnen, wurde an diesen Fettorganen gleichzeitig der chemische DNS-Gehalt (Ermittlung der Gesamtzellzahl), eine Fettzelldurchmesserbestimmung (Errechnung der Fettzellzahl) und zytophotometrische Messungen (Ermittlung des DNS-Gehaltes der Einzelzelle und der Ploidiestufe) durchgeführt.