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Biomedical subjects

C Kaiser

Publications and source records attributed to C Kaiser.

At least 91 records · Page 5Linked to original sources
PubMed1988

Nasal septal carcinoma: initial symptom of nasal septal perforation.

A case of a primary squamous cell carcinoma of the nasal septum in a young female with initial symptom of septal perforation is reported. Carcinoma of the nasal septum is an uncommon entity and there are a few cases reported in the literature. The functional impact of their treatment and the high mortality makes it important to diagnose it at early stage. We discuss the differential diagnosis of septal perforation and recommend early wide surgical excision.

Adult↗
PubMed1987

Multisubstrate inhibitors of dopamine beta-hydroxylase. 2. Structure-activity relationships at the phenethylamine binding site.

1-Aralkylimidazole-2-thiones have been shown to be potent multisubstrate inhibitors of dopamine beta-hydroxylase (DBH; EC 1.14.17.1). In the present study, a series of 1-benzylimidazole-2-thiones was prepared to explore the effects of substitution in the benzyl ring on the inhibition of DBH. A detailed structure-activity relationship for in vitro activity was discovered and this was shown by a modified Hansch analysis to correlate (r = 0.91) with four key structural features of the benzyl ring: the presence of a hydroxyl at the 4-position, molar refractivity at the 3-, 4-, and 5-positions, inductive effects of the substituents at the 3-, 4-, and 5-positions, and pi-electron density. The affinity (Kis) of eight substituted inhibitors for DBH was shown to correlate (r = 0.75) with the affinity (KD) of comparably substituted tyramines for the ternary DBH-oxygen-tyramine complex. This correlate is used to support the hypothesis that binding of inhibitor to DBH occurs in a fashion that mimics the binding of tyramine substrates. The most potent inhibitors were selected for study in vivo in the spontaneously hypertensive rat model of hypertension. The changes in vascular dopamine and norepinephrine levels that resulted from oral administration of the inhibitors corresponded to the observed reduction in mean arterial blood pressure. A divergence between in vitro potency and in vivo efficacy upon oral dosing was noted and is suggested to result from an in vivo metabolic conjugation of the phenolic group of inhibitor.

Animals↗
PubMed1987

Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines.

To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to a suitably oriented aromatic ring (i.e., in an axial orientation approximately orthogonal to the catechol nucleus) in agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) that are selective for this subtype, cis- and trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared. These compounds are 5,6-ethano-bridged derivatives of the D-1 selective dopamine receptor agonist 1. Introduction of the bridge reduces the conformational mobility of the parent molecule. Comprehensive conformational analyses by molecular mechanical methods indicated that both the cis and trans isomers could attain a conformation that places the phenyl substituent in an axial orientation. X-ray analysis of the trans isomer showed an axial disposition of the phenyl ring; however, NMR studies suggest that this conformation is fixed in the trans isomer, but not in the cis. The dopamine receptor binding affinity and intrinsic activity of the cis isomer were considerably greater than those of its trans counterpart; the cis isomer also demonstrated a high degree of selectivity for the D-1 subtypes. One possible explanation of these results, suggested by the molecular modeling studies, is that both the axial orientation of the phenyl postulated to be required for binding to the receptor and a putatively requisite location of the nitrogen in approximately the plane of the catechol ring can be attained only by the cis isomer in which the tetrahydroazepine ring is in a twist conformation. Conversely, these results might simply suggest a preference of the D-1 receptors for benzazepine agonists having the phenyl group in an equatorial orientation. Still another possibility is that the D-1 receptor binding site is in a sterically hindered area accessible only to compounds that are relatively planar. However, it requires an axial 1-phenylbenzazepine for strong binding. Thus, a conformationally flexible cis isomer could more readily achieve the different conformations required to both gain access to and bind with the D-1 site.

Animals↗
PubMed1987

Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist.

We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions.

Alkylating Agents↗
PubMed1986

[125I]SCH 23982: the ligand of choice for identifying the D-1 dopamine receptor.

[125I]SCH 23982, [125I]8-iodo-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol, binds reversibly and with high affinity (Kd = 0.7 +/- 0.05 nM) to specific binding sites (maximum binding = 108 +/- 3.5 fmol/mg) in the caudate nucleus of the rat brain. The caudate binding site displays pharmacological properties similar to the D-1 receptor; furthermore, the site has a low affinity for drugs favoring the D-2 receptor. GTP diminishes the affinity of dopamine, a D-1 agonist, but not SCH 23390, a D-1 antagonist, for the caudate binding site. The iodinated ligand discriminates between the D-1 and the D-2 dopamine receptors: the neurointermediate lobe of the rat pituitary gland, a tissue rich in D-2 dopamine receptors, possesses less than 4% of the specific binding sites in the caudate. Because [125I]SCH 23982 exists at a higher specific activity than [3H]SCH 23390, a ligand used previously to identify the D-1 receptor, and because the results obtained with the iodinated ligand are otherwise similar to those obtained with the [3H]SCH 23390, [125I]SCH 23982 is the ligand of choice for identifying the D-1 receptor.

Adenylyl Cyclases↗
PubMed1986

Syntheses and in vitro evaluation of 4-(2-aminoethyl)-2(3H)-indolones and related compounds as peripheral prejunctional dopamine receptor agonists.

A series of (beta-aminoethyl)indolones and related compounds was synthesized and evaluated in vitro as peripheral prejunctional dopaminergic agonists in the field-stimulated isolated perfused rabbit ear artery. 4-[2-(Di-n-propylamino)ethyl]-7-hydroxy-2(3H)-indolone was the most potent compound (ED50 = 2 +/- 0.3 nM) tested, while the related secondary amine 24 and the des-OH derivatives 28 and 34 were only slightly less potent. 4-Methoxybenzeneethanamine and 2-methyl-3-nitrophenylacetic acid were employed as starting materials for for the synthesis of the 4-(beta-aminoethyl)indolones. The ring-opened 3-acylamino analogues 46 and 47 were prepared via nitration of the phenethylamine 43 derived from 4-methoxyphenylacetic acid. The inactive isomeric indolones 38, 39, and 41 were derived from 4-nitrobenzeneethanamine and from indolone-6-acetic acid.

Animals↗
PubMed1986

Synthesis and dopaminergic activity of some halogenated mono- and dihydroxylated 2-aminotetralins.

In a series of 7,8-dihydroxy-1-phenyltetrahydro-3-benzazepine dopamine receptor agonists introduction of a chloro or fluoro substituent into the 6-position increases dopaminergic potency. Also, in this series replacement of the 7-hydroxyl group with a halogen results in inversion of activity from dopamine receptor agonist to antagonist. The present study was aimed at exploring the possibility that the structure-activity observations in the 3-benzazepine series of dopaminergic agents might be extrapolated to another class of dopamine receptor agonists, the 2-aminotetralins. Thus, a series of chloro- and fluoro-substituted mono- and dihydroxylated 2-aminotetralins was prepared and evaluated for dopaminergic properties in D-1 and D-2 receptor-related tests. Introduction of a chloro substituent into the 8-position of the prototype of this series, i.e. 2-amino-6,7-dihydroxytetralin (ADTN), resulted in a compound with a high degree of selectivity for the D-1 subpopulation of dopamine receptors; it was equally or more potent than ADTN in the D-1 receptor-related tests with greatly decreased effectiveness in the tests involving D-2 receptors. A similar effect was observed with 8-fluoro-ADTN; however, the N-(4-hydroxyphenethyl)-N-propyl derivative 4g of the 8-chloro-substituted ADTN showed marked D-2 binding affinity. Conversely, introduction of a chloro substituent into the 5-position of ADTN markedly decreased D-1 receptor affinity and efficacy. This effect was not seen with the related 5-fluoro derivative, suggesting D-1 receptors are more sensitive to bulk in the 5-position of ADTN than are the D-2 receptors. Replacement of either the 6- or 7-hydroxyl groups of ADTN with a chloro or fluoro substituent, in contrast, did not parallel the response seen in the benzazepine series (i.e., the compounds uniformly demonstrated less receptor affinity and did not have dopamine receptor antagonist activity); however, the decrease in agonist potency was less marked in the case of 2-amino-6-fluoro-7-hydroxytetralins than in the chlorinated monohydroxyaminotetralins. Thus, a parallelism in structure-activity relationships in the benzazepine and aminotetralin series of dopamine receptor agonists was not observed. The differences may reflect altered modes of receptor binding in the two series.

Animals↗
PubMed1986

6,7-Dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline . A structurally novel beta-adrenergic receptor blocking agent.

Replacement of the catecholic hydroxyl groups of the beta-adrenergic receptor agonist 6,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (trimetoquinol) with chloro substituents results in a compound with marked beta-adrenoceptor antagonist properties. This, therefore, parallels the similar transformation of the beta-adrenoreceptor agonist isoproterenol into the antagonist dichloroisoproterenol. In a test for inhibition of isoproterenol-induced enhancement of the rate of contraction of spontaneously beating guinea pig atrial pairs the resultant 6,7-dichloro-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline (6b) had a KB value of (6.7 +/- 2.3) X 10(-8) M. Although this is nearly 2 orders of magnitude less potent than propranolol (KB = 6.2 X 10(-10) M in this test), this compound represents the prototype of a new class of beta-adrenergic receptor blockers, and unlike dichloroisoproterenol it is not a partial agonist. It has physicochemical properties, e.g., pKa and distribution and partition coefficients, that differ from the prototypic beta-blockers. These altered properties might impart advantageous tissue distribution and altered pharmacological properties to the new molecule. This new beta-adrenoreceptor antagonist is suggested to merit further study.

Adrenergic beta-Antagonists↗
PubMed1986

Multisubstrate inhibitors of dopamine beta-hydroxylase. 1. Some 1-phenyl and 1-phenyl-bridged derivatives of imidazole-2-thione.

The synthesis and characterization of some 1-(phenylalkyl)imidazole-2-thiones as a novel class of "multisubstrate" inhibitors of dopamine beta-hydroxylase (DBH) are described. These inhibitors incorporate structural features that resemble both tyramine and oxygen substrates, and as evidenced by steady-state kinetics, they appear to bind both the phenethylamine binding site and the active site copper atom(s) in DBH. A series of structural congeners that incorporate different bridging chain lengths between the phenyl ring (dopamine mimic) and the imidazole-2-thione group (oxygen mimic) define the optimum distance for inhibitory potency and the likely intersite distance in the DBH active site. Additional bridging analogues were prepared to determine the active site bulk tolerance and the effects of heteroatom replacement.

Animals↗
PubMed1985

Characterisation of calmodulin from Drosophila heads.

Calmodulin from Drosophila heads has been purified to apparent electrophoretic homogeneity. It has the same characteristics as bovine brain calmodulin with respect to the migration upon polyacrylamide gel electrophoresis and maximal activation of a calmodulin-deficient cAMP phosphodiesterase. The amino acid composition resembles bovine brain calmodulin with the exception that trimethyllysine is absent and that it contains only one tyrosine. The tryptic peptide map of Drosophila calmodulin suggests some differences in the amino acid sequence as compared to bovine brain calmodulin. These proposed differences in the primary structure may explain why Drosophila calmodulin is less potent than bovine brain calmodulin in the activation of a cAMP phosphodiesterase from bovine brain.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1985

Distinction of viral and host-derived glycopolypeptides induced by "early" functions of human cytomegalovirus.

Human cytomegalovirus is shown to induce in phosphonoacetic acid-treated human fibroblasts glycosylation of five polypeptides with approximate molecular weights of 200-250, 150, 135, 130 and 100 kilodaltons (kd). Except for the 130 kd product, these glycopolypeptides (gp) separate with the cytoplasmic fraction, only one (200-250 kd) with the chromatin fraction as well. The gp of 135 and 100 kd were found to be virus-specified as determined by immunoblotting and immunoprecipitation. The gp of 200-250 kd exhibited an immunological relatedness to fibronectin and are therefore considered host-specific products. Both subsets of gp participate in virus-induced surface membrane alterations as documented by living cell immunofluorescence.

Antigens, Surface↗
PubMed1985

[The persistence of activity of H1N1 (swine) influenza virus in pig breeding units during non-epidemic phases].

A study is carried on in a group of 16 commercial breeding-finishing units in Brittany (France). The aim of this study is to try to reveal the persistence of activity of the Influenza Virus within these intensive units after an acute epizootic. In each farm two batches of pigs are selected, individually identified and followed from suckling period to slaughter. Serological controls are conducted every month on the same pigs. Both Influenza and Aujeszky's disease antibodies are apprehended. Furthermore nasal swabs and lungs are submitted to analysis for virus isolation purposes and data are collected from each herd for epidemiological studies. Influenza passive H.I. Antibodies rapidly decrease in the piglets. Later a seroconversion is observed in 10% of the investigated piglets. These pigs belong to 4 herds. The conversion happens usually after 3 months of age. All attempts to isolate the virus failed. Special herd conditions may be associated with a persistence of the viral activity inside the units between epizootics: bad demography (unbalance in the breeding stock), inadequate hygiene policy in the fattening house (with permanent arrivals of pigs coming from subsequent batches of sows), a high prevalence of respiratory and specially pulmonary enzootic diseases. A seroconversion against Aujeszky's disease is pointed out in 3 out of the 4 herds concerned with Influenza virus activity suggesting that closely the same conditions may be related both to influenza and Aujeszky's disease virus activity.

Animals↗