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  • 1
    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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  • 2
    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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  • 3
    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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  • 4
    Electronic Resource
    Electronic Resource
    Synthesis of the selective antimuscarinic agent 4-{[cyclohexylhydroxy(2-methoxyphenyl)silyl]-methyl}-1,1-dimethylpiperazinium methyl sulfate (o-methoxy-sila-hexocyclium methyl sulfate) (1989)
    New York, NY [u.a.] : Wiley-Blackwell
    Applied Organometallic Chemistry 3 (1989), S. 129-132 
    Details
    ISSN: 0268-2605
    Keywords: o-methoxy-sila-hexocyclium ; sila-hexocyclium ; sila-drugs ; antimuscarinics ; muscarinic receptor subtypes ; Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The synthesis of the potent and highly selective silicon-containing antimuscarinic agent o-methoxysila-hexocyclium methyl sulfate and its corresponding tertiary amine (isolated as the dihydrochloride) is described. The quarternary compound is an o-methoxy derivative of sila-hexocyclium methyl sulfate, which represents one of the tools currently used in experimental pharmacology for the subclassification of muscarinic receptors. The o-methoxy derivative, the pharmacological profile of which differs substantially from that of the nonmethoxy compound, is also recommended as a tool for the investigation of muscarinic receptor heterogeneity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1002/aoc.590030203
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  • 5
    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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  • 6
    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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  • 7
    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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