Bibliothek

X
feed icon rss

Ihre E-Mail wurde erfolgreich gesendet. Bitte prüfen Sie Ihren Maileingang.

Leider ist ein Fehler beim E-Mail-Versand aufgetreten. Bitte versuchen Sie es erneut.

Vorgang fortführen?

Exportieren
Filter
  • Organic Chemistry  (7)
  • Muscarinic receptor subtypes  (4)
  • M4 receptors  (2)
  • Difenidol, p-fluoro-hexahydro-, enantiomers of  (1)
  • Key words Rat anococcygeus muscle  (1)
  • Key words: Endogenous noradrenaline release – Rabbit vas deferens – Prejunctional muscarinic inhibition – Muscarinic receptor subtypes – Prejunctional purinoceptors – P2 purinoceptor antagonist – Prostanoids  (1)
Datenquelle
Materialart
Erscheinungszeitraum
Schlagwörter
  • 1
    Digitale Medien
    Digitale Medien
    Characterization of postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 671-677 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Key words Rat anococcygeus muscle ; Muscarinic ; receptor subtypes ; Muscarinic agonists ; Muscarinic ; antagonists ; M3 receptors ; Stereoselectivity ; Hexahydro-difenidol
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The present study was designed to characterize the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle by means of a series of muscarinic agonists and subtype-preferring key muscarinic antagonists. Cumulative addition of muscarinic agonists elicited concentration-dependent contractions with the following rank order of potency (pD2 values): (+)-muscarine (6.36) ≥ oxotremorine M (6.21) ≥ arecaidine propargyl ester (APE) (6.18) 〉 carbachol (5.68)=(±)-methacholine (5.65) 〉 4-(4-chlorophenyl-carbamoyloxy)-2-butynyltrimethylammonium chloride (4-Cl-McN-A-343) (4.28) 〉 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343) (3.89). (+)-Muscarine, oxotremorine M, carbachol and (±)-methacholine behaved as full agonists, whereas APE, 4-Cl-McN-A-343 and McN-A-343 displayed partial agonism. The contractile responses of the rat anococcygeus muscle to (±)-methacholine were competitively antagonized by pirenzepine (pA2=6.92), 11-[[4-[4-(diethylamino)butyl]-1-piperidinyl]acetyl] 5,11-dihydro-6H-pyrido(2,3-b)(1,4)-benzodiazepine-6-one (AQ-RA 741; pA2=6.75), himbacine (pA2=7.11), (±)-p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD; pA2=7.68) and the (R)- and (S)-enantiomers of hexahydro-difenidol [(R)-HHD: pA2=8.52; (S)-HHD: pA2=6.06]. A comparison of the pA2 values derived from studies of contraction in rat anococcygeus muscle with literature binding (pKi values) and functional affinities (pA2 values) obtained at native M1-M4 receptors strongly suggests that the postjunctional muscarinic receptors mediating contraction in rat anococcygeus muscle are of the M3 subtype.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/PL00005104
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 2
    Digitale Medien
    Digitale Medien
    Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 342 (1990), S. 284-289 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Muscarinic receptors ; M4 receptors ; Guinea-pig uterus ; Pirenzepine ; Methoctramine ; Sila-hexocyclium
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The present study was designed to further characterize the muscarinic receptors mediating contraction of the guinea-pig uterus. The affinities of various selective muscarinic antagonists were determined and compared with those obtained at M1 (rabbit vas deferens), M2 (guinea-pig atria) and M3 receptors (guinea-pig ileum). The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD2 = 5.73) were competitively antagonized by pirenzepine (pA2 = 7.04), AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]- 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzo. diazepin-6-one) (pA2 = 6.96), himbacine (pA2 = 7.92), methoctramine (pA2 = 7.52), 4-DAMP (4-diphenylacetoxy-N-methylpiperidine methiodide) (pA2 = 8.87) and sila-hexocyclium (pA2 = 8.81). A comparison of affinity values indicates that the muscarinic receptors present in guinea-pig uterus display a novel pharmacological profile which is not consistent with the presence of either an M1, M2 or M3 receptor. The affinities determined for the different antagonists rather showed a close similarity to those obtained at muscarinic receptors present in rat striatum and NG108-15 cells which are considered pharmacological equivalents (M4 receptors) of the m4 gene product. We thus hypothesize that the guinea-pig isolated uterus preparation may serve as a simple functional assay system to study the pharmacology of M4 receptors.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00169439
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 3
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Methoctramine ; Polymethylene tetraamines ; Cardioselectivity ; M1/M2 receptors ; Muscarinic receptor subtypes
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00173395
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 4
    Digitale Medien
    Digitale Medien
    Evidence for muscarinic M4 receptors mediating nonadrenergic noncholinergic relaxations in rabbit anococcygeus muscle (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 505-516 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Key words Rabbit anococcygeus muscle ; Muscarinic receptor subtypes ; Nicotinic receptors ; Nitric oxide (NO) ; NANC relaxation ; M4 receptors ; Nitric oxide synthase inhibitors
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract The aim of the present study was to characterize the muscarinic receptor subtype mediating nonadrenergic noncholinergic (NANC) relaxations in the rabbit anococcygeus muscle (RAM) by the use of muscarinic receptor agonists and a battery of key muscarinic antagonists. In addition, experiments were carried out to identify the NANC neurotransmitter(s) involved in the inhibitory NANC neurotransmission. In preparations with histamine-raised tone, the non-selective muscarinic agonists (pD2 values) (+)-muscarine (5.23), cis-dioxolane (5.16), oxotremorine M (4.95) and carbachol (4.06) produced concentration-dependent relaxations corresponding to 72.6–85.0% of the histamine-induced precontraction. In contrast, the subtype-preferring (M1/M4 over M2 and M3 receptors) agonists 4-(3-chlorophenylcarbamoyloxy)-2-butynyltrimethylammonium chloride (McN-A-343), (S)-4-(dimethylamino)-1-methyl-2-butynyl-N-(3-chlorophenyl)carbamate methobromide [(S)-BN 228], (R)- and (S)-N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide [(R)- and (S)-BM 5] showed no or rather low [(S)-BN 228] muscarinic activity. The low potencies, together with the ineffectiveness of some agonists, indicated a low effective receptor reserve associated with the relaxant response. No contractile responses to (+)-muscarine were observed neither in unstimulated nor in precontracted preparations suggesting that the existence of an excitatory postjunctional muscarinic receptor may be excluded. The nicotinic antagonist hexamethonium had no influence on relaxant responses to (+)-muscarine, but abolished relaxations elicited by (–)-nicotine. This demonstrates that the RAM contains also nicotinic acetylcholine receptors (AchRs) mediating inhibitory NANC responses. Relaxations induced by the stimulation of muscarinic and nicotinic AchRs as well as by electrical field stimulation (EFS) were completely abolished by tetrodotoxin and were also sensitive to the nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NOARG), indicating that NO plays an important role as an inhibitory NANC transmitter in RAM. All muscarinic antagonists investigated did not influence the histamine-induced precontraction, but shifted the concentration-response curve of (+)-muscarine to the right in a parallel fashion. Schild analysis yielded regression lines of unit slope, indicating competitive antagonism. The following rank order of antagonist potencies (pA2 values) was found: 11-({4-[4-(diethylamino)-bu-tyl]-1-piperidinyl}-acetyl-5,11-dihydro-6H-pyrido (2,3-b) (1,4)-benzodiazepine-6-one hydrochloride (AQ-RA 741; 8.08) = himbacine (8.03) ≥ tripitramine (7.69) ≥ p-fluoro-hexahydro-sila-difenidol (p-F-HHSiD; 7.48) ≥ methoctramine (7.30) ≥ pirenzepine (7.18) ≥ guanylpirenzepine (6.24). A comparison of the pA2 values determined in the RAM with published data from binding studies at muscarinic M1–M4 and m5 receptors suggests that the functional muscarinic receptor mediating NANC relaxation in the RAM is of the M4 subtype. Taken together, the results obtained in the present study provide convincing evidence that relaxant responses elicited by muscarinic stimuli in RAM are nitrergic in nature and mediated by muscarinic M4 receptors located somadendritically on NANC neurons. Thus, the isolated RAM may serve as a functional muscarinic M4 receptor model.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/PL00005084
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 5
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Endogenous noradrenaline release ; Rabbit vas deferens ; Prejunctional muscarinic inhibition ; Muscarinic receptor subtypes ; Prejunctional purinoceptors ; P2 purinoceptor antagonist ; Prostanoids
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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 Al receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the P2 purinoceptor antagonist pyridoxalphosphate-6-azophenyl-2′,4′-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-butynylN-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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00178199
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 6
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Key words: Endogenous noradrenaline release – Rabbit vas deferens – Prejunctional muscarinic inhibition – Muscarinic receptor subtypes – Prejunctional purinoceptors – P2 purinoceptor antagonist – Prostanoids
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: 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.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00178199
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 7
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): phenglutarimide enantiomers ; enantioselectivity ; antiparkinsonian drugs ; M1-selective antagonists ; rabbit vas deferens ; pirenzepine ; Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: 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.
    Zusätzliches Material: 1 Ill.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1002/chir.530010212
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 8
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Beschreibung / Inhaltsverzeichnis: 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.
    Notizen: 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.
    Zusätzliches Material: 1 Ill.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1002/jlac.198319830605
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 9
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Difenidol, (R)- and (S)-hexahydro- ; Antimuscarinic properties ; Muscarinic receptor subtypes ; Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Beschreibung / Inhaltsverzeichnis: 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.
    Notizen: 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.
    Zusätzliches Material: 4 Ill.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1002/jlac.198919890128
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
  • 10
    Digitale Medien
    Digitale Medien
    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
    Schlagwort(e): Difenidol, p-fluoro-hexahydro-, enantiomers of ; Muscarinic receptors, subtypes of ; Chemistry ; Organic Chemistry
    Quelle: Wiley InterScience Backfile Collection 1832-2000
    Thema: Chemie und Pharmazie
    Notizen: 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).
    Zusätzliches Material: 2 Ill.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1002/jlac.199119910196
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
    Artikel (Nationallizenzen)
    Volltext
Schließen ⊗
Diese Webseite nutzt Cookies und das Analyse-Tool Matomo. Weitere Informationen finden Sie hier...