@article{TackeLinohErnstetal.1987,
  author    = {Tacke, Reinhold and Linoh, H. and Ernst, L. and Moser, U. and Mutschler, E. and Sarge, S. and Cammenga, H. K. and Lambrecht, G.},
  title     = {Darstellung und Eigenschaften der Enantiomere der Antimuskarinika Sila-Procyclidin und Sila-Tricyclamol-iodid: Optisch aktive Silanole mit Silicium als Chiralit{\"a}tszentrum},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63822},
  year      = {1987},
  abstract  = {Durch Racematspaltung mit L-( + )- bzw. o-(-}-Weins{\"a}ure wurden die Enantiomere des Sila-Procyclidins (R}-1 b und (S}-1 b erhalten (>97\% ce (NMR), 99.7\% ee {DSC)]. Daraus wurden die Hydrochloride (R}-2b und (S)-lb und durch Umsetzung mit CH31 die Enantiomerc des Sila-Tricyclamol-iodids (R)-3b und (S}-3b [>96\% ee (NMR)] hergestelll Die optisch aktiven Silanoie sind in k:ristalliner Form und in inerten L{\"o}sungsmitteln konfigurationsstabil. w{\"a}hrend sie in w{\"a}sseriger L{\"o}sung raoemisieren (3 b schneller als 111). In. Analogie zur Stereoselektivit{\"a}t der antimuskarin. iscben Wirkung der Enantiomere der Kohlenstoff-Analoga Procyclidin (la) und Tricyclamol-iodid (3a) besitzen die (R)Enantiomere von 1 b und 311 eine gr{\"o}ßere Affinit{\"a}t zu den ilealen M2\&- und atrialen M2ar-Muskarinrezeptorcn des Meerschwein,;, cbens als die (S)-Antipoden. Alle Silicium-Verbindungen sind st{\"a}rker antiinuskarinisch wirksam als ihre Kohlenstoff-Analoga, deren Stereoselektivit{\"a}t jedoch st{\"a}rker ausgepr{\"a}gt ist. Die Unterschiede in der A1Tmit{\"a}t von (R}-1 b und (S)-1 b zu den ilealen und atrialen Muskarinrezeptoren best{\"a}tigen das Konzept der Heterogenit{\"a}t musk:arinis.cher M 2-Rezeptoren (M 2\(_\alpha\): atrialer Typ; M2\(_\beta\): ilealer Typ).},
  subject      = {Anorganische Chemie},
  language  = {de}
}
@article{TackeStrohmannSargeetal.1989,
  author    = {Tacke, Reinhold and Strohmann, C. and Sarge, S. and Cammenga, H. K. and Schomburg, D. and Mutschler, E. and Lambrecht, G.},
  title     = {Darstellung und Eigenschaften der Enantiomere des selektiven Antimuscarinikums 1-Cyclohexyl-1-phenyl-4-piperidino-1-butanol (Hexahydro-Difenidol)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63950},
  year      = {1989},
  abstract  = {No abstract available},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{StrohmannBauereckerCammengaetal.1991,
  author    = {Strohmann, C. and Bauerecker, S. and Cammenga, H. K. and Jones, P. G. and Mutschler, E. and Lambrecht, G. and Tacke, Reinhold},
  title     = {Enantiomers of the muscarinic antagonist 1-cyclohexyl-1-(4-fluorophenyl)-4-piperidino-1-butanol (p-fluoro-hexahydro-difenidol): synthesis, absolute configuration, and enantiomeric purity},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64144},
  year      = {1991},
  abstract  = {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-fl uorophen yl)-4-piperidino- 2-butyn-1-ol [(R)- and (S)-4]. Reaction of (R)-2a and (S)-2a with rnethyl iodide led to (R)-3 and (S)-3, respectively. The unsaturated precursors (R)- and (S}-4 (enantiorneric purity ~ 99.80 and ~99.94\% e.e.; calorimetric analysis) were prepared by res-sepaolution of rac-4 [available from 4-FC\(_6\)H\(_4\)C(O)C\(_6\)H\(_{11}\) by reaction with LiC ~ CCH\(_2\)NC\(_5\)H\(_{10}\)] 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 rnuscarinic receptor research (affinity profile: M1 ~ M3 ~ M4 > M2).},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{KoppLambrechtMutschleretal.1989,
  author    = {Kopp, R. and Lambrecht, G. and Mutschler, E. and Moser, U. and Tacke, Reinhold and Pfeiffer, A.},
  title     = {Human HT-29 colon carcinoma cells contain mucarinic M\(_3\) receptors coupled to phosphoinositide metabolism},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63989},
  year      = {1989},
  abstract  = {Five different musearlnie receptor subtypes ean be distinguished by the differenees in their amino aeid sequence, the eoupled signal transduetion system, pharmaeologieal binding properties and aetivation of ionie fluxes. The present study served to eharaeterize the binding profile of musearlnie receptors in human eolon eareinoma eells (HT-29) using seleetive musearlnie antagonists. The affinities of the compounds were eompared with their poteney to inhibit cholinergieally-aetivated phosphoinositide metabolism. Pirenzepine displaced [\(^3\)H]N-methyl-scopolamine binding and inhibited inositolphosphate (IP) release with potencies typieal of those of non-M\(_1\) receptors. The M\(_3\) subtype-selective antagonists sila-hexocyelium and hexahydro-sila-difenidol bad high affinity to the musearlnie reeeptors in HT-29 cells (K0 = 3.1 nM and 27 nM, respectively) and inhibited IP release at nanomolar concentrations. The M\(_2\) receptor antagonists, AF-DX 116 and methoctramine, had low antimusearinic poteneies. Our results demonstrate that HT-29 human colon earcinoma cells contain an apparently pure population of M\(_3\) receptors. These cells could serve as a model system for further investigations coneerning regulatory and signal transduction mechanisms associated with glandular muscarinic M\(_3\) receptors.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{VerspohlTackeMutschleretal.1990,
  author    = {Verspohl, E. J. and Tacke, Reinhold and Mutschler, E. and Lambrecht, G.},
  title     = {Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63993},
  year      = {1990},
  abstract  = {Cholinergie agents arepotent modulators of insulin release that aet via musearinie reeeptors. We now investigated the muscarinic receptor subtype present in rat panereatic islets in binding and funetional studies. Binding of 5 nM [ \(^3\)H]N-methylscopolamine ([\(^3\)H]NMS) was half maximal at 30 min. At 60 min, the maximal total bindingwas 1.29\% and the non-specifie binding (presence of 100 ,uM atropine) was 0.18\% of the total radioaetivity per 10 f.'g islet protein. Unlabelled atropine inhibited [\(^3\)H]NMS binding with an IC50 of ca. 30 nM. The rank order of antagonist high-affinity binding was atropine > sila-hexocyelium methyl sulfate (SiHC; M\(_1\) > M\(_3\) > M\(_2\) ) > pirenzepine (M\(_1\)> M\(_2\) = M\(_3\) ) = methoctramine (M\(_2\) > M\(_1\) > M\(_3\) ). The high-affinity K\(_d\)s were 8.5, 56, 1300 and 1300 nM, respectively. The high affinity Kd of the muscarinie receptor agonist, arecaidine propargyl ester (APE), was 8.1 nM. The EC\(_{50}\) for the biologieal effects of APE on insulin and glucagon secretion was 3.2 and 2.3 nM. The rank order for the high-affinity biological effects of antagonists (inhibition of APE-mediated insulin/ glucagon release) was almost the same as for binding. The data indicate that rat pancreatie islets contain neither an M\(_1\) subtype (high-affinity for pirenzepine) nor an M\(_2\) subtype (high-affinity for methoctramine) receptor. However, the data evidence an M\(_3\) receptor subtype, since SiHC in the absence of the M\(_1\) receptor subtype shows a relatively high affinity to the receptors in rat panereatic islets.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{DoerjeFriebeTackeetal.1990,
  author    = {D{\"o}rje, F. and Friebe, T. and Tacke, Reinhold and Mutschler, E. and Lambrecht, G.},
  title     = {Novel pharmacological profile of muscarinic receptors mediating contraction of the guinea-pig uterus},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64071},
  year      = {1990},
  abstract  = {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 M\(_1\) (rabbit vas deferens), M\(_2\) (guinea-pig atria) and M\(_3\) receptors (guinea-pig ileum). The contractile responses of uterine smooth muscle from immature guinea-pigs to carbachol (pD\(_2\) = 5.73) were competitively antagonized by pirenzepine (pA\(_2\) = 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) (pA\(_2\) = 6.96), himbacine (pA\(_2\) = 7.92), methoctramine (pA\(_2\) = 7.52), 4-DAMP (4-diphenylacetoxy- N-methylpiperidine methiodide) (pA\(_2\) = 8.87) and sila-hexocyclium (pA\(_2\) = 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 M\(_1\), M\(_2\) or M\(_3\) 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 (M\(_4\) 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 M\(_4\) receptors.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{LambrechtGmelinRafeineretal.1988,
  author    = {Lambrecht, G. and Gmelin, G. and Rafeiner, K. and Strohmann, C. and Tacke, Reinhold and Mutschler, E.},
  title     = {o-Methoxy-sila-hexocyclium: a new quaternary M\(_1\)-selective muscarinic antagonist},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63862},
  year      = {1988},
  abstract  = {No abstract available},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{LambrechtFeifelForthetal.1988,
  author    = {Lambrecht, G. and Feifel, R. and Forth, B. and Strohmann, C. and Tacke, Reinhold and Mutschler, E.},
  title     = {p-Fluoro-hexahydro-sila-difenidol: the first M\(_{2\beta}\)-selective muscarinic antagonist},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63872},
  year      = {1988},
  abstract  = {No abstract available},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{RettenmayrRodriguesdeMirandaRijntjesetal.1990,
  author    = {Rettenmayr, N. M. and Rodrigues de Miranda, J. F. and Rijntjes, N. V. M. and Russel, F. G. M. and van Ginneken, C. A. M. and Strohmann, C. and Tacke, Reinhold and Lambrecht, G. and Mutschler, E.},
  title     = {Pharmacokinetic properties of the antimuscarinic drug [\(^3\)H]-hexahydro-sila-difenidol in the rat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64022},
  year      = {1990},
  abstract  = {The pharmacokinetics of tritiated hexahydrosila- difenidol ([\(^3\)H]-HHSiD) were examined in rats. Furthermore, the distribution of radioactivity was studied by means of whole body autoradiography. After i. v. administration of 2.9 mg/kg HHSiD plus [\(^3\)H]-HHSiD to anaesthetized rats bearing a catheter implanted in the ductus choledochus and receiving a mannitol infusion, HHSiD was rapidly distributed and metabolized. Only 5\% ofthe radioactivity was recovered in blood after 23 s and 0.4\% after 2.5 h. 64\% of the plasma radioactivity could be extracted with hexane from the samples taken 23 s after administration. 52\% of the radioactivity was eliminated within 2.5 h, 13\% by urinary and 39\% by biliary excretion. Following oral administration of 8.6 mg/kg HHSiD plus [\(^3\)H]-HHSiD there was an absorption of approximately one fourth of the administered radioactivity within 4 h. By means of whole body autoradiography (i. v. injection) as well as by tissue distribution measurement the highest Ievels of radioactivity were found in bile, urine, lung, kidney, adrenals, liver and .pancreas. Thus, after i. v. administration to rats HHSiD is rather quickly distributed, metabolized and excreted. This explains its low antimuscarinic potency in vivo.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{EltzeGmelinWessetal.1988,
  author    = {Eltze, M. and Gmelin, G. and Wess, J. and Strohmann, C. and Tacke, Reinhold and Mutschler, E. and Lambrecht, G.},
  title     = {Presynaptic muscarinic receptors mediating inhibition of neurogenic contractions in rabbit vas deferens are of the ganglionic M\(_1\)-type},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63912},
  year      = {1988},
  abstract  = {The present study was designed to further charaeterize the presynaptie musearlnie M\(_1\)-reeeptor responsible for the inhibition of neuragenie eontraetions in the isolated rabbit vas deferens. Eleetrically induced twiteh eontraetions of this preparation were inhibited by the M\(_1\)-agonist, MeN-A-343, and by some of its analogs: 4-ehloro-phenyl derivative> MeN-A-343 > trans-olefinie analog> cis-olefinie analog. The same rank order of potency was observed for these agonists to raise the blood pressure of pithed rats by stimulation of M\(_1\)-receptors in sympathetie ganglia. A highly signifieant eorrelation was found between the antimusearinie potencies of atropine, pirenzepine and a series of 9 antagonists strueturally related to the ganglionie M\(_{1\beta}\)-receptor selective compounds, hexocyclium and hexahydro-difenidol, to antagonize the MeN-A-343-indueed inhibition of twitch eontraetions in rabbit vas deferens or the musearine-indueed depolarization in rat isolated superior eerVieal ganglia. It is suggested that the presynaptie musearlnie receptor that mediates inhibition of neuragenie contraetions in rabbit vas deferens is of the ganglionic M\(_{1\beta}\)-type.},
  subject      = {Anorganische Chemie},
  language  = {en}
}