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  • Organic Chemistry  (7)
  • Cardioselectivity  (1)
  • Key words: Endogenous noradrenaline release – Rabbit vas deferens – Prejunctional muscarinic inhibition – Muscarinic receptor subtypes – Prejunctional purinoceptors – P2 purinoceptor antagonist – Prostanoids  (1)
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  • 1
    Electronic Resource
    Electronic Resource
    Methoctramine selectively blocks cardiac muscarinic M2 receptors in vivo (1988)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 338 (1988), S. 246-249 
    Details
    ISSN: 1432-1912
    Keywords: Methoctramine ; Polymethylene tetraamines ; Cardioselectivity ; M1/M2 receptors ; Muscarinic receptor subtypes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The antimuscarinic effects of methoctramine (N, N′- bis[6-[(2-methoxybenzyl)amino]hexyl]-1,8-octanediamine tetrahydrochloride), a polymethylene tetraamine endowed with high cardioselectivity in vitro, were assessed in two in vivo preparations. Methoctramine (300 μg/kg i.v.) strongly inhibited the methacholine- and muscarine-induced bradycardia in the anaesthetized and pithed rat, respectively. The same dose of methoctramine did not significantly affect the depressor action of methacholine in the anaesthetized rat mediated by vascular M2 receptors. Furthermore, even high doses of methoctramine (up to 1 mg/kg i. v.) did not reduce the ganglionic M1 receptor-mediated tachycardia and pressor response to muscarine or McN-A-343 in the pithed rat. These data suggest that methoctramine while showing high affinity for cardiac M2α receptors has rather low affinity for ganglionic M1 and vascular M2 receptors. This in vivo study thus provides further evidence to support the view that methoctramine is a potent and highly selective antagonist of cardiac M2α receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00173395
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  • 2
    Electronic Resource
    Electronic Resource
    Characterization of the prejunctional muscarinic receptors mediating inhibition of evoked release of endogenous noradrenaline in rabbit isolated vas deferens (1994)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 349 (1994), S. 1-10 
    Details
    ISSN: 1432-1912
    Keywords: Key words: Endogenous noradrenaline release – Rabbit vas deferens – Prejunctional muscarinic inhibition – Muscarinic receptor subtypes – Prejunctional purinoceptors – P2 purinoceptor antagonist – Prostanoids
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The aim of the present study was to characterize the prejunctional modulation of evoked release of endogenous noradrenaline in rabbit vas deferens by the use of muscarinic receptor agonists and subtype-prefering antagonists.   Vasa deferentia of the rabbit were stimulated electrically by trains of 120 pulses delivered at 4 Hz or trains of 30 pulses at 1 Hz. The inhibition by muscarinic agonists of the stimulation-evoked overflow of endogenous noradrenaline in the absence and presence of antagonists was used to determine affinity constants for antagonists. These values were compared with those observed at putative M1 receptors inhibiting neurogenic twitch contractions in the rabbit vas deferens and with affinity data obtained at M1(m1)–M4(m5) receptors in functional studies and binding experiments.   The evoked overflow of noradrenaline from sympathetic nerves was enhanced by the A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-29,49-disulfonic acid (PPADS) and indomethacin, indicating a tonic inhibition by endogenous A1 and P2 purinoceptor agonists and prostanoids, respectively. The stimulation-evoked overflow at 4 Hz was not sensitive to inhibition by the muscarinic agonists methacholine or 4-(4-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium iodide (4-Cl-McN-A-343). In contrast, at a stimulation frequency of 1 Hz the evoked noradrenaline release was decreased by muscarinic agonists (EC50): arecaidine propargyl ester (0.062 μM), 4-Cl-McN-A-343 (0.32 μM), 4-(4-fluorophenylcarbamoyloxy)-2-butynyl-N-methyl-pyrrolidinium tosylate (4-F-PyMcN+; 0.48 μM) and methacholine (0.86 μM). The affinity constants of most of the muscarinic antagonists [atropine: pKB = 9.47; (R)-trihexyphenidyl: pKB = 9.18; pirenzepine: pA2 = 7.68; methoctramine: pKB = 6.90] are consistent with estimates of these antagonists at M1(m1) receptors determined in various functional and binding studies. The high antagonistic potency of pirenzepine and (R)-trihexyphenidyl and the agonistic activity of 4-F-PyMcN+ argue for the involvement of M1, and against that of M2 and M3 receptors in the inhibition of evoked noradrenaline overflow. However, the high apparent pKB of 8.30 for himbacine is not in accordance with an M1 receptor; by contrast, it would be compatible with the presence of M2 or M4 receptors. The potencies of the tested muscarinic agonists and antagonists largely agree with those obtained for the inhibition of neurogenic twitch responses (0.05 Hz) in the rabbit vas deferens. In conclusion, the rabbit vas deferens is endowed with prejunctional muscarinic receptors mediating heteroinhibition of noradrenaline release that are probably of the same subtype as the putative M1 receptors inhibiting neurogenic twitch contractions, and are not of the M2, M3 or m5 subtype.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00178199
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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    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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  • 8
    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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  • 9
    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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