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  • 1
    Electronic Resource
    Electronic Resource
    In vitro and in vivo irreversible plasma protein binding of beclobric acid enantiomers (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 120-125 
    Details
    ISSN: 0899-0042
    Keywords: beclobrate ; beclobric acid ; acyl glucuronides ; hydrolysis ; isomerization ; irreversible binding ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Acyl glucuronides are known to be labile conjugates, which undergo hydrolysis and bind irreversibly to proteins. The lipid-regulating agent (±)-beclobrate is immediately converted to the free acid after oral administration. Further metabolism leads to formation of the corresponding diastereomeric acyl glucuronides. Beclobric acid glucuronides were quantified by indirect measurement with an HPLC method based on chiral fluorescent derivatization of the carboxylic acid and subsequent normal-phase chromatography. The renal clearance of unchanged drug is low, with almost all drug excreted into urine as glucuronic acid conjugates. Beclobric acid glucuronide is also detectable in plasma. In vitro degradation studies with beclobric acid glucuronide (at a concentration of 5 μM in 150 mM phosphate buffer pH 7.4) exhibited a minor tendency for acyl migration and hydrolysis, i.e., a higher stability than has been observed for the acyl glucuronides of most other drugs. The in vitro degradation half-lives of the two beclobric acid β-1-O-acyl glucuronides were 22.7 and 25.7 h. After incubation with pooled plasma and human serum albumin in buffer pH 7.4 irreversible binding was measured in vitro. No significant difference between the two enantiomers was detected with respect to the magnitude of in vitro irreversible binding. In 3 healthy male volunteers the extent of irreversible binding of both beclobric acid enantiomers to plasma proteins was investigated after single and multiple oral doses of racemic beclobrate (100 mg once daily). Irreversible binding of both enantiomers was observed in all volunteers. The adduct densities for (-)- and (+)-beclobric acid after single 100 mg beclobrate doses were 0.147 × 10-4 and 0.177 × 10-4 mol/mol protein. Multipie dosing increased irreversible binding 3- to 4-fold. © 1993 Wiley-Liss, Inc.
    Additional Material: 6 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530050304
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  • 2
    Electronic Resource
    Electronic Resource
    Direct enantiospecific HPLC bioanalysis of (R,S)-atenolol on a chiral stationary phase (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 479-482 
    Details
    ISSN: 0899-0042
    Keywords: chiral resolution ; high-performance liquid chromatography (HPLC) ; β-blocker ; cellulose ; Tris-3,5-dimethylphenylcarbamate ; chiral stationary phase ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The simultaneous determination of the enantiomers of the β1-selective adrenergic antagonist atenolol in human plasma and urine is described. After an alkaline preextraction atenolol is extracted from biological material at pH 12.3 using dichloromethane/propan-2-ol. The separation of the underivatized enantiomers is achieved by high-performance liquid chromatography on a chiral stationary phase (Chiralcel OD, cellulose tris-3, 5-dimethylphenylcarbamate, coated on silica gel) with fluorimetric detection. (-)-(S)-Pindolol is used as an internal standard. The detection limits of 5 ng/ml enantiomer in plasma and 50 ng/ml enantiomer in urine are sufficient for pharmacokinetic studies after therapeutic doses. © 1993 Wiley-Liss, Inc.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530050614
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  • 3
    Electronic Resource
    Electronic Resource
    Rats with portacaval shunt as a potential experimental pharmacokinetic model for liver cirrhosis: Application to carvedilol stereopharmacokinetics (1993)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 5 (1993), S. 1-7 
    Details
    ISSN: 0899-0042
    Keywords: enantiomers ; conjugates ; protein binding ; tissue binding ; stereoselective pharmacokinetics ; first-pass effect ; drug metabolism ; liver disease ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: As an experimental model for reduced liver function rats with surgical portacaval shunts (pcs) may be used. Carvedilol, a nonselective β-adrenoceptor antagonist with vasodilating activity, is extensively metabolised by phase I as well as phase II pathways. In order to study the stereoselective pharmacokinetics of carvedilol in liver disease, pcs and control rats were given rac-carvedilol intravenously and p.o. The carvedilol enantiomers and their conjugates were assayed in plasma, urine, and bile. Carvedilol was highly bound to plasma proteins; binding was reduced by pcs. In all groups, the plasma concentrations of (R)-carvedilol exceeded those of (S)-carvedilol significantly. In comparison to the control group the plasma concentrations of both enantiomers increased after pcs, while the difference between the stereoisomers decreased. The total clearance decreased proportionally to the decrease in liver weight (30%). Both the apparent oral clearance, as well as its stereoselectivity were reduced, by up to 90 and 43%, respectively. The biliary clearance of the parent drug after i.v. dosage increased in rats with pcs due to the reduced hepatic metabolism. © 1993 Wiley-Liss, Inc.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530050102
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  • 4
    Electronic Resource
    Electronic Resource
    Pharmacokinetic studies with the lipid-regulating agent beclobrate: Enantiospecific assay for beclobric acid using a new fluorescent chiral coupling component (S-FLOPA) (1991)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 3 (1991), S. 35-42 
    Details
    ISSN: 0899-0042
    Keywords: chiral derivatization ; pharmacokinetics ; enantiospecific assay ; fluorescent derivatization ; flunoxaprofen ; acyl glucuronides ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The major biotransformation pathway for the chiral lipid-regulating agent beclobrate is conversion to the corresponding carboxylic acid, which is then metabolized to the acyl glucuronide. An enantiospecific assay for biological material was developed that is based on chiral derivatization with N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDAC) and the primary amine S-FLOPA, a new chiral coupling component for carboxylic acids derived from the 2-arylpropionic acid S-flunoxaprofen. Conversion of beclobric acid to the acyl chloride prior to coupling with the amine is also feasible. From plasma or urine beclobric acid was extracted into n-hexane/ethanol (9:1) at pH 4 after addition of sodium chloride. Clofibric acid was used as internal standard. Derivatization with EDAC/FLOPA was performed under addition of 1-hydroxybenzotriazole in anhydrous dichloromethane containing trace amounts of pyridine (ambient temperature/2 h reaction time). The chromatographic separation was performed on a silica gel stationary phase (Zorbax Sil) using n-hexane-chloroform-ethanol (100:10: 0.75, by vol) as mobile phase [flow rate, 2 ml/min; fluorescence detection, 305/355 nm; elution order of the derivatives, (-) before (+)]. Coefficients of variation were between 1.3 and 9.3% for both plasma and urine. Limit of quantification was 20-25 ng/ml for plasma based on a sample volume of 0.2 ml. Application of the assay in a pilot pharmacokinetic study showed significant differences between the kinetics of the two enantiomers. In plasma and urine, the concentrations of the dextrorotatory enantiomer exceeded those of the levorotatory enantiomer significantly.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530030108
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  • 5
    Electronic Resource
    Electronic Resource
    Stereoselectivity at muscarinic receptor subtypes: observations with the enantiomers of phenglutarimide (1989)
    New York, NY [u.a.] : Wiley-Blackwell
    Chirality 1 (1989), S. 170-173 
    Details
    ISSN: 0899-0042
    Keywords: phenglutarimide enantiomers ; enantioselectivity ; antiparkinsonian drugs ; M1-selective antagonists ; rabbit vas deferens ; pirenzepine ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The affinity of the enantiomers of phenglutarimide at three muscarinic receptor subtypes was examined in vitro using field-stimulated rabbit vas deferens (M1 receptors) and guinea pig atria (M2α receptors) and ileum (M2β receptors). Extremely high stereoselectivity was observed and higher affinities (up to 6000-fold) were found for the (+)-S-enantiomer. The stereoselectivity ratios were different at the three subtypes, and the stereochemical demands made by the muscarinic receptors were most stringent at M1 receptors. (+)-(S)-Phenglutarimide was found to be a potent M1-selective antagonist (pA2 at M1 = 8.53). Its receptor selectivity profile is qualitatively similar to that of pirenzepine. (-)-(R)-Phenglutarimide showed no comparable discriminatory properties.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/chir.530010212
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  • 6
    Electronic Resource
    Electronic Resource
    Sila-Pharmaka, 30. (2-Aminoethyl)cycloalkylphenylsilanole: Bioisosterer C/Si-Austausch bei Parasympatholytika vom Typ des Trihexyphenidyls, Cycrimins und Procyclidins (1983)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1983 (1983), S. 922-930 
    Details
    ISSN: 0170-2041
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Sila-Pharmaca, 30. - (2-Aminoethyl)cycloalkylphenylsilanols: Bioisosteric C/Si Exchange in Parasympatholylics of the Trihexyphenidyl, Cycrimine, and Procyclidine TypeThe synthesis of the (2-aminoethyl)cycloakylphenylsilanols 5b (sila-trihexyphenidyl), 6b (Sila-cycrimine), 7b (sila-procyclidine), and 8b is described. Starting with CI2(C6H5)SiCh—CH2(9), 5b-8b were obtained by five reaction steps with a total yield of 32-40%. The C/Si pairs 5a,b-8a,b, were tested for antimuscarinic activity on the isolated guinea-pig ileum. The increase of affinity of the muscarinic receptor caused by sila-substitution of 5a-8a is less marked than in the case of the structurally related C/Si 1a,b-4a,b.
    Notes: Die Synthese der (2-Aminoethyl)cycloalkylphenylsilanole 5b (Sila-Trihexyphenidyl), 6b (Sila-Cycrimin), 7b (Sila-Procyclidin) und 8b wird beschrieben. 5b-8b wurden - ausgehend von Ci2(C?6H5)SiCCCCH—CH2 (9) - durch eine fünfstufige Reaktionsfolge mit einer Gesamtausbeute von 32-40% erhalten. Am isolierten Ileum des Meerschweinchens wurden die C/Si-Paare 5a,b-8a,b vergleichend auf ihre antimuskarinische Aktivität geprüft. Die durch die Sila-Substitution von 5a-8b erreichte Zunahme der Affinität zum Muskarinrezeptor ist deutlich weniger ausgeprägt als bei den strukturverwandten C/Si-Paaren 1a,b-4a,b.
    Additional Material: 1 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.198319830605
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  • 7
    Electronic Resource
    Electronic Resource
    Darstellung und Eigenschaften der Enantiomere des selektiven Antimuscarinikums 1-Cyclohexyl-1-phenyl-4-piperidino-1-butanol (Hexahydro-Difenidol) (1989)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1989 (1989), S. 137-143 
    Details
    ISSN: 0170-2041
    Keywords: Difenidol, (R)- and (S)-hexahydro- ; Antimuscarinic properties ; Muscarinic receptor subtypes ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Preparation and Properties of the Enantiomers of the Selective Antimuscarinic Agent 1-Cyclohexyl-1-phenyl-4-piperidino-1-butanol (Hexahydro-Difenidol)Using (S)- or (R)-mandelic acid as the resolving agent, the enantiomers of 1-cyclohexyl-1-phenyl-4-piperidino-2-butin-1-ol [(R)-2 and (S)-2] were prepared (enantiomeric purity: ee = 99.7%; calorimetric analysis). Catalytic hydrogenation (Pd/C contact) of (R)-2 and (S)-2 yielded the enantiomers of 1-cyclohexyl-1-phenyl-4-piperidino-1-butanol [(R)- and (S)-hexahydro-difenidol, (R)-1a and (S)-1a] which were isolated as hydrochlorides [(R)-1a ⋅ HCl and (S)-1a ⋅ HCl, ee = 99.7%]. The absolute configuration of the enantiomers of 1a and 2 was determined by an X-ray crystal structure analysis of the mandelate (S)-1a ⋅ (R)-C6H5CH(OH)COOH. (R)-Hexahydro-difenidol [(R)-1a] and (R)-2 exhibit a higher affinity for the atrial M2α and ileal M2β muscarinic receptors of the guinea pig than the respective antipodes (S)-1a and (S)-2 (atrial stereoselectivity index: 17 and 8.6, respectively; ileal stereoselectivity index: 193 and 44, respectively). In addition, (R)-1a and (R)-2 exhibit a significantly higher affinity for the M2β receptors of the ileum than for the M2α receptors of the atrium (atrium/ileum ratio: 21 and 10, respectively). Thus, (R)-1a and (R)-2 are valuable tools for the identification and characterization of muscarinic M2 subtypes. In contrast, the less potent (S)-enantiomers of 1a and 2 do not differentiate between M2α and M2β receptors.
    Notes: Durch Racematspaltung mit (S)- bzw. (R)-Mandelsäure wurden die Enantiomere von 1-Cyclohexyl-1-phenyl-4-piperidino-2-butin-1-ol [(R)-2 und (S)-2] dargestellt (Enantiomerenreinheit: ee = 99.7%, kalorimetrische Analyse). Katalytische Hydrierung (Pd/C-Kontakt) von (R)-2 und (S)-2 ergab die Enantiomere von 1-Cyclohexyl-1-phenyl-4-piperidino-1-butanol [(R)- und (S)-Hexahydro-Difenidol, (R)-1a und (S)-1a], die als Hydrochloride (R)-1a ⋅ HCl und (S)-1a ⋅ HCl isoliert wurden (ee = 99.7%). Die absolute Konfiguration der Enantiomere von 1a und 2 wurde durch Röntgenkristallstrukturanalyse des Mandelats (S)-1a ⋅ (R)-C6H5CH(OH)COOH bestimmt. (R)-Hexahydro-Difenidol [(R)-1a] und (R)-2 besitzen eine höhere Affinität zu den atrialen M2α-und ilealen M2β-Muscarinrezeptoren des Meerschweinchens als die entsprechenden Antipoden (S)-1a und (S)-2 (atrialer Stereoselektivitätsindex: 17 bzw. 8.6; ilealer Stereoselektivitätsindex: 193 bzw. 44). Darüber hinaus besitzen (R)-1a und (R)-2 eine signifikant höhere Affinität zu den M2β-Rezeptoren des Ileums als zu den M2α-Rezeptoren des Atriums und sind somit wertvolle Modellverbindungen zur Identifizierung und Charakterisierung von muscarinischen M2-Subtypen (Atrium/Ileum-Quotient: 21 bzw. 10). Im Gegensatz hierzu vermögen die schwächer wirksamen (S)-Enantiomere von 1a und 2 nicht zwischen den M2α- und M2β-Rezeptoren zu unterscheiden.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.198919890128
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  • 8
    Electronic Resource
    Electronic Resource
    Enantiomers of the muscarinic antagonist 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-1-butanol (p-fluoro-hexahydro-difenidol): Synthesis, absolute configuration, and enantiomeric purity (1991)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1991 (1991), S. 523-527 
    Details
    ISSN: 0170-2041
    Keywords: Difenidol, p-fluoro-hexahydro-, enantiomers of ; Muscarinic receptors, subtypes of ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The enantiomers of the antimuscarinic agent 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-1-butanol [(R)- and (S)-p-fluorohexahydro-difenidol] [(R)- and (S)-2a] and their methiodides (R)-3 and (S)-3 were prepared with high enantiomeric purity. (R)-2a and (S)-2a (isolated as hydrochlorides) were obtained by catalytic hydrogenation (Pd/C contact) of the corresponding enantiomers of 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-2-butyn-1-ol [(R)- and (S)-4]. Reaction of (R)-2a and (S)-2a with methyl iodide led to (R)-3 and (S)-3, respectively. The unsaturated precursors (R)- and (S)-4 (enantiomeric purity ≥99.80 and ≥99.94% e.e.; calorimetric analysis) were prepared by resolution of rac-4 [available from 4-FC6H4C(O)C6H11 by reaction with LiC≡CCH2NC5H10] using (R)- and (S)-mandelic acid as resolving agents. The absolute configurations of the (R) and (S) enantiomers of 2a, 3, and 4 were determined by an X-ray crystal-structure analysis of (S)-5, the methiodide of (S)-4. (R)-2a and (R)-3 exhibit a higher affinity for muscarinic M1, M2, M3, and M4 receptors (by up to two orders of magnitude) than their corresponding antipodes (S)-2a and (S)-3, the degree of stereoselectivity depending on the receptor subtype involved. (R)-2a represents a useful tool for muscarinic receptor research (affinity profile: M1 ≈ M3 ≈ M4 〉 M2).
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.199119910196
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  • 9
    Electronic Resource
    Electronic Resource
    Sila-Pharmaka, 33. Synthese und Eigenschaften des selektiven Antimuskarinikums Cyclohexylphenyl-(3-piperidinopropyl)silanol (1985)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1985 (1985), S. 2223-2228 
    Details
    ISSN: 0170-2041
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Sila-Pharmaca, 33.  -  Synthesis and Properties of the Selective Antimuscarinic Agent Cyclohexylphenyl(3-piperidinopropyl)silanolThe synthesis of the selective antimuscarinic agent cyclohexylphenyl(3-piperidinopropyl)silanol (1b) is described. Starting with (3-chloropropyl)trimethoxysilane, 1b was obtained by four reaction steps and isolated as hydrochloride 2b with a total yield of about 45%.  -  Because of its high pharmacological selectivity 1b has become a reference drug in experimental pharmacology for the differentiation of muscarinic receptors.
    Notes: Die Synthese des selektiven Antimuskarinikums Cyclohexylphenyl(3-piperidinopropyl)silanol (1b) wird beschrieben. 1b wurde - ausgehend von (3-Chlorpropyl)trimethoxysilan - durch eine vierstufige Reaktionsfolge erhalten und als Hydrochlorid 2b mit einer Gesamt-ausbeute von etwa 45% isoliert.  -  1b ist aufgrund seiner großen pharmakologischen Selektivität zu einer Standardsubstanz in der experimentellen Pharmakologie bei der Differenzierung von Muskarinrezeptoren geworden.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.198519851112
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  • 10
    Electronic Resource
    Electronic Resource
    Zur absoluten Konfiguration der Enantiomere der Antimuskarinika Procyclidin und Tricyclamoliodid: Röntgen-strukturanalyse von (R)-1-[3-Cyclohexyl-3-hydroxy-3-phenyl-propyl]-1-methylpyrrolidiniumiodid (1986)
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 1986 (1986), S. 242-250 
    Details
    ISSN: 0170-2041
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: On the Absolute Configuration of the Enantiomers of the Antimuscarinic Agents Procyclidine and Tricyclamol Iodide: X-Ray Structural Analysis of (R)-1-[3-Cyclohexyl-3-hydroxy-3-phenyl-propyl]-1-methylpyrrolidinium IodideThe absolute configurations of the antimuscarinic agents procyclidine (1a) and tricyclamol iodide (2a) were established by X-ray structural analysis of (R)-1-[3-Cyclohexyl-3-hydroxy-3-phenyl-propyl]-1-methylpyrrolidinium iodide [(R)-tricyclamol iodide, (R)-2a]. The antimuscarinic potency of (R)-1a and (R)-2a is about 380 and 90 times, respectively, greater than that of the corresponding (S)-configurated enantiomers (guinea-pig ileum).
    Notes: Durch Röntgenstrukturanalyse von (R)-1-[3-Cyclohexyl-3-hydroxy-3-phenylpropyl]-1-methyl-pyrrolidiniumiodid [(R)-Tricyclamoliodid, (R)-2a] wurden die absoluten Konfigurationen der Enantiomere der Antimuskarinika Procyclidin (1a) und Tricyclamoliodid (2a) bestimmt. (R)-1a und (R)-2a sind etwa 380-bzw. 90mal stärker antimuskarinisch wirksam (isoliertes Meerschweinchen-Ileum) als die entsprechenden (S)-konfigurierten Enantiomere.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/jlac.198619860204
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