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Biomedical subjects

C Kaiser

Publications and source records attributed to C Kaiser.

At least 127 records · Page 7Linked to original sources
PubMed1982

Absolute stereochemistry and dopaminergic activity of enantiomers of 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine.

Resolution of the unique dopamine receptor agonist 2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine (1) was achieved by a stereospecific multistep conversion of the readily separated enantiomers of its O,O,N-trimethylated precursor 2. The absolute stereochemistry of the antipodes of 2-MeI was determined by single-crystal X-ray diffractometric analysis, thus permitting assignment of the configuration of stereospecifically related 1, as well as that of the synthetic intermediates. High-performance liquid chromatography of diastereoisomeric derivatives was utilized to determine the enantiomeric excess of the R (greater than 97%) and S (greater than 89%) isomers of 1. Examination of the isomers in several in vitro and in vivo tests for both central and peripheral dopaminergic activity revealed that activity resided almost exclusively in the R isomer. The results suggest that the properly oriented 1-phenyl substituent of 1 is important for dopamine-like activity; it may contribute to receptor binding by interaction with a chirally defined accessory site. Configurational and conformational requirements for receptor binding of 1 are considered in relationship to previously described dopaminergic agents. These studies, in accord with previous suggestions, indicate that (R)-1 interacts with dopamine receptors in a conformation in which the catecholic hydroxyls and basic nitrogen are at least nearly maximally separated.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed1981

Amaranth suppresses the mutagenicity of 2-acetylaminofluorene by lowering the concentration of NADPH in top agar.

Addition of 1 mg amaranth (FD&C Red No. 2) to the top agar of Salmonella/S9 assay plates decreased the yield of revertants induced by 20 micrograms 2-acetylaminofluorene (AAF) by over 50% and additional amaranth completely eliminated the mutagenic response. Similar suppression of AAF mutagenicity was seen with sulfonazo III, another azo dye. The suppressive effect of amaranth was greatest at low S9 concentrations and decreased as the amount of S9 was increased. When N-hydroxyacetylaminofluorene (N-OH-AAF) was used as mutagen, amaranth had little or no effect on either the number of revertants obtained or the S9 optimum. Similarly, 1-naphthylamine-4-sulfonic acid (a reduction product of amaranth) did not significantly affect the mutagenicity of AAF. The rate of metabolism of [14C]AAF by the S9 preparations was shown to be markedly decreased by amaranth, as were the levels of both the phenolic metabolites and of N-OH-AAF. Thus, it appeared that amaranth acts by blocking the conversion of AAF to N-OH-AAF and that this effect is caused by the amaranth itself and not by its constituent amines. Further experiments indicated that amaranth greatly decreased the levels of NADPH formed in reaction mixtures comparable to S0 mix in top agar and that such reaction mixtures also metabolized amaranth to colourless compounds. It appears likely that in top agar, NADPH reacts with amaranth at a fast enough rate to limit severely the level of the reduced co-factor (which must be formed from NADPH+ by the action of endogenous glucose-6-phosphate dehydrogenase) and thus decreases the rate of activation of mutagens by other NADPH-dependent processes.

2-Acetylaminofluorene↗
PubMed1980

Inhibitors of phenylethanolamine N-methyltransferase and epinephrine biosynthesis. 1. Chloro-substituted 1,2,3,4-tetrahydroisoquinolines.

In a search for inhibitors of epinephrine biosynthesis as potential therapeutic agents, a series of 13 ring-chlorinated 1,2,3,4-tetrahydroisoquinolines was prepared. These compounds were tested initially for their ability to inhibit rabbit adrenal phenylethanolamine N-methyltransferase (PNMT) in vitro. Enzyme-inhibitor dissociation constants, determined for the six most potent members of the series, indicated the following order of decreasing potency: 7,8-Cl2 greater than 6,7,8-Cl3 greater than 7-Cl approximately 5,6,7,8-Cl4 greater than 5,7,8-Cl3. These compounds were subsequently examined for PNMT-inhibiting activity in intact rats and mice. 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (13, SK&F 64139) was the most potent member of the series both in vitro and in vivo and is currently undergoing clinical investigation.

Adrenal Glands↗
PubMed1979

[Diptera of Calliphora genus, potential carriers and spreaders of swine vesicular disease virus].

Swine Vesicular Disease virus ingested by the adult fly Calliphora persists several days in the digestive tract of the insect and is eliminated in feces. The virus ingested by the insect at larval stage has been recovered from the digestive tract and feces of adult flies. Thus, the dissemination of the virus, even in a limited fashion, seems to be possible and attention is chiefly centered on the second process.

Animals↗
PubMed1979

[In-vitro-technique for autoradiographic investigations of cell proliferation in benign and malignant alterations of the human urinary bladder mucosa from biopsy specimens (author' transl)].

An in-vitro double labelling technique with 3H- AND 14C-Thymidine was applied to biopsy specimens of the human urinary bladder mucosa in order to determine proliferation kinetics of normal bladder epithelium as well as its benign and malignant alterations. Application of above mentioned technique led to evaluable autoradiographs. The mean 3H-Thymidine labelling-index in bladder cancer was remarkably higher than in normal bladder epithelium and in benign papillomas. There was a good correlation between histologic grading of malignancy and increase of the mean 3H-Thymidine labelling index. Addition of 5-Fluorodesoxyuridine to the incubation medium had no influence on the labelling of the incubated tissue.

Autoradiography↗
PubMed1978

Studies on renal dopamine receptors with a new agonist.

SK & F 38393 (2,3,4,5-tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine) is a new dopamine receptor agonist which selectively increased renal blood flow when administered i.v. to dogs at cumulative doses of 3.3-1333 microgram/kg. Consistent changes in arterial blood pressure heart rate and cardiac output were not observed. The renal response, which was mediated locally in the kidney, was not antagonized by adequate blocking doses of atropine, propranolol, metiamide and/or mepyramine nor by reserpinization or treatment with indomethacin. It was inhibited, however, by the selective peripheral dopamine receptor antagonist, bulbocapnine. Perhaps as a result of its action on renal blood flow, SK & F 38393 produced a diuresis in normally hydrated rats which was characterized by an increased excretion of sodium, potassium and chloride and a increased urinary pH. Compounds of this type may be useful in better defining dopaminergic receptors and in the treatment of disease states where renal ischemia is present.

Animals↗
PubMed1978

Genetics of nitrofurazone resistance in Escherichia coli.

Wild-type Escherichia coli cells are sensitive to nitrofurazone (NF) and many other nitrofuran derivatives. A variety of evidence indicated that these compounds are converted to toxic "active" metabolites by reductases present in the bacteria. Sensitive E. coli K-12 acquired threefold-greater resistance to NF in one mutational step. These partially resistant mutants could undergo a second mutation that made them 10 times as resistant as the wild type. Mutation of wild-type strain K-12 to the higher level of resistance in a single step was not observed. The first mutational step was associated with partial loss of reduced nicotinamide adenine dinucleotide phosphate-linked, O(2)-insensitive NF reductase activity, and the second step was associated with loss of the remaining activity. The two-step mutants did, however, contain other NF reductases that were inhibited by O(2) and reduced NF only under anaerobic conditions. We designated the genes that control reductase activity "nitrofuran sensitivity genes" (nfsA and nfsB). Thus, wild-type strains are nfsA(+)nfsB(+), and the resistant double mutants are nfsA nfsB. A variety of crosses established that these genes are both located close to gal, that the most probable sequence is lac nfsB gal nfsA, and that the single-step mutants with an intermediate level of resistance are nfsA nfsB(+). The nfsA(+)nfsB strains contained about 70 to 80% of the wild-type reductase I activity-apparently enough to confer wild-type sensitivity. This reductase activity was resistant to 2 M urea. The nfsA nfsB(+) strains had only 20 to 30% of the wild-type activity, and this residual activity was sensitive to 2 M urea.

Crosses, Genetic↗
PubMed1978

[The position of scintigraphy in traumatology].

A report on the findings of skeletal scintigraphy in 80 cases of traumatic bone lesions is discussed. After a short survey on the physiological process in the activity ensilage, the assertion of the scintigraphy is compared to the X-ray. The indication which has been approved in practice is discussed and described. In correct indication scintigraphy is a valuable diagnostic measure and it may influence the procedure.

Adult↗
PubMed1978

[Scintigraphy in the diagnosis of osteitis].

The report on the experience with skeletal scintigraphy in case of osteitis discusses the clinical use of this method. It is shown that with correct indication scintigraphy can furnish early diagnosis and in many cases additional valuable information.

Adult↗
PubMed1977

Adrenergic agents. 4. Substituted phenoxypropanolamine derivatives as potential beta-adrenergic agonists.

A series of 1-(substituted phenoxy)-3-(tert-butylamino)-2-propanols in which the ring substituents were 3,4-dihydroxy (6f), 3- and 4-hydroxy (6g and 6h, respectively), 3-hydroxy-4-methylsulfonamido (6i), its 3,4-transposed isomer (6j), and 4-methylsulfonylmethyl (6k) was prepared and examined for beta-adrenergic agonist and/or antagonist properties. Two of these compounds, 6f and 6j, were potent beta-adrenoreceptor agonists in in vitro tests that measure a compound's ability to relax guinea pig tracheal smooth muscle and to increase the rate of contraction of guinea pig right atria. Several compounds had a dose-dependent effect. Although they produced potent beta-adrenergic agonist activity at low concentrations, 6g, 6h, and 6j antagonized the effects of a standard beta-adrenoreceptor agonist at higher concentrations. The methylsulfonylmethyl derivative 6k produced beta-adrenergic blocking effects as demonstrated by attenuation of isoproterenol-induced increases in the rate of contraction of an isolated rabbit heart preparation. On the basis of these pharmacological results, coupled with NMR spectral data, it appears that the previous suggestion that aryloxypropanolamines interact with beta-adrenocreceptors as a consequence of their ability to assume an orientation in which the benzene ring the ethanolamine moieties can be superimposed on those of corresponding adrenergic phenylethanolamines is invalid. An alternative "bicyclic" rigid conformation involving two intramolecular hydrogen bonds in the protonated form of the aryloxypropanolamines is suggested to account for the similar beta-adrenoreceptor activity of these compounds and related phenylethanolamines.

Adrenergic beta-Agonists↗
PubMed1977

Adrenergic agents. 5. Conformational analysis of 1-alkylamino-3-aryloxy-2-propanols by proton magnetic resonance studies. Implications relating to the steric requirements of adrenoreceptors.

Two distinct chemical classes, namely, phenylethanolamines resembling the natural biogenic catecholamines and 1-alkylamino-3-aryloxy-2-propanols (aryloxpropanolamines), exert a distinct action as agonists and/or antagonists of adrenergic receptors. To explore the possibility that these two different kinds of chemicals might share a common ground-state conformation as an essential structural feature that satisfies the specific steric requiremetns for the active site of the receptor, a conformational analysis of some aryloxypropanolamines and related compounds was performed. On the basis of this NMR conformational analysis it is suggested that salts of 1-alkylamino-3-aryl-oxy-2-propanols in a nonpolar solvent may exist in a stable "rigid" conformation involving two intramolecular hydrogen bonds to form a 6-5 bicyclic chelated structure. Comparison of steremodels of this "rigid" bicyclic conformer with the conformationally preferred trans (phenyl to amino) rotamer of adrenergic phenylethanolamines, such as isoproterenol, indicates that all positions of the phenyl ring, the phenyl to oxygen or phenyl to carbon bonds, and the ammonium groups of both chemical classes may be superimposed nearly exactly. A major difference between the two species is the relative steric orientation of the alcoholic hydroxyl groups which are about 2 A removed when models of the two classes of adrenergic agents are superimposed. That a specific steric orientation of this alcoholic functionality may not be an absolute requirement for adrenergic activity is supported by the recent observation of significant activity in the homologue of N-tert-butylnorepinephrine in which a methylene group is inserted between the benzylic carbon and the hydroxyl group. Possibly the different steric location of the alcoholic hydroxyl group may be involved in the altered beta1- and beta2-adrenoreceptor selectivity of phenylethanolamines and phenoxypropanolamines.

Hydrogen Bonding↗
PubMed1977

Adrenergic agents. 6. Synthesis and potential beta-adrenergic agonist activity of some meta-substituted p-hydroxyphenylethanolamines related to salbutamol.

Salbutamol, an adrenergic receptor agonist with selectivity for tracheobronchial vs. cardiac muscle, differs from the catecholamine N-tert-butylnorepinephrine in that it bears a hydroxymethyl, rather than a phenolic, group in the meta position. In a search for new bronchodilating agents with minimal cardiovascular side effects, a series of derivatives, in which this m-hydroxymethyl group is modified, was prepared. These compounds were examined for potential bronchodilator activity in an in vitro test that measures relaxation of guinea pig tracheal smooth muscle. Potential cardiac stimulant activity was evaluated in vitro by monitoring changes in the rate of contraction of spontaneously beating guinea pig right atria. Although many of these compounds retained a high degree of potency, all were less effective than salbutamol in the tracheal test. Several of the derivatives, notably ones bearing 1-hydroxyethyl (1d), 1,2-dihydroxyethyl (1f), 1-hydroxy-2-methoxyethyl (1g), and 2-hydroxy-1-methoxyethyl (1h) substituents in place of the parent's m-hydroxymethyl group, however, were considerably more selective for tracheobronchial vs. cardiac muscle in the in vitro tests utilizing guinea pig tracheal and right atrial muscle.

Adrenergic beta-Agonists↗
PubMed1977

Adrenergic agents. 8.1 Synthesis and beta-adrenergic agonist activity of some 3-tert-butylamino-2-(substituted phenyl)-1-propanols.

Replacement of the benzylic hydroxyl group of N-tert-butylnorepinephrine with a hydroxymethyl substituent affords a propanolamine homologue which retains a high degree of beta-adrenergic agonist activity. As modification of the meta substituent of catecholic ethanolamines, such as N-tert-butylnorepinephrine, often provides compounds that exert a more pronounced effect in relaxing tracheobronchial smooth muscle (beta2-adrenergic agonist) than in stimulating cardiac muscle (beta1-adrenergic response), a series of 3-tert-butylamino-2-(3-substituted 4-hydroxyphenyl)-1-propanols was prepared. The 3-meta substituents included HOCH2 (1b), H2NCONH (1c), MeSO2NH (1d), H (le), and NH2 (1f). These phenylpropanolamine derivatives were compared with their phenylethanolamine counterparts in in vitro tests that measure the ability of these compounds to relax spontaneously contracted guinea pig tracheal smooth muscle (a measure of potential bronchodilating activity) and to increase the rate of contraction of a spontaneously beating guinea pig right atrial preparation (an indicator of potential cardiac stimulating activity). In these tests all of the propanolamine derivatives included in the study were less potent than their ethanolamine relatives. In both series replacement of the catecholic m-hydroxyl group with the indicated substituents usually resulted in compounds with increased selectivity for tracheobronchial vs. cardiac muscle.

Adrenergic beta-Agonists↗