@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}
}
@article{PolidoriMassiLambrechtetal.1990,
  author    = {Polidori, C. and Massi, M. and Lambrecht, G. and Mutschler, E. and Tacke, Reinhold and Melchiorre, C.},
  title     = {Selective antagonists provide evidence that M\(_1\) muscarinic receptors may mediate carbachol-induced drinking in the rat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64044},
  year      = {1990},
  abstract  = {The present study served to investigate the ability of seven selective muscarinic antagonists to inhibit carbachol-induced drinking in the rat. The muscarinic antagonists were given by intracerebroventricular (i.c.v.) injection 1 min before the i.c.v. injection of carbachol (1 \(\mu\)g/rat). The M\(_2\) antagonist, methoctramine, was inactive up to 80.3 nmol/rat. The M\(_3\) antagonist, p-fluoro-hexahydro-sila-difenidol, elicited a modest (42\%) but statistically significant inhibition of drinking only at 80 nmol/rat. On the other band, the selective M\(_1\) antagonists, (R)-trihexyphenidyl, o-methoxy-sila-hexocyclium and pirenzepine, produced a marked and dose-dependent inhibition of carbachol-induced drinking, their 1050 values being 0.51. 7.36 and 9.31 nmoljrat. Also the M\(_1\)/M\(_3\) antagonists, 4-diphenylacetoxy-Nmethylpiperidine methiodide and hexahydro-sila-difen.idol, were potent inhibitors of carbachol-induced drinking, their ID\(_50\) values (0.28 and 11.09 nmoljrat) being related to their pA\(_2\) values for M1 receptors in rabbi t vas deferens. These data suggest that carbachol-induced drinking may be mediated by activation of muscarinic M\(_1\) receptors.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{FeifelRodriguesdeMirandaStrohmannetal.1991,
  author    = {Feifel, R. and Rodrigues de Miranda, J. F. and Strohmann, C. and Tacke, Reinhold and Aasen, A. J. and Mutschler, E. and Lambrecht, G.},
  title     = {Selective labelling of muscarinic M\(_1\) receptors in calf superior cervical ganglia by [\(^3\)H](\(\pm\))-telenzepine},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64082},
  year      = {1991},
  abstract  = {A method was developed to detennine the affinities of antimuscarinic drugs at M\(_1\) receptors. [\(^3\)H](±)-Telenzepine served as radioligand in crude preparations of calf superior cervical ganglia and showed high affinity for a single receptor population. consisting of M1 receptors (K\(_D\) = 1.12 nM). Kinetic experiments showed monophasic association (k\(_1\) =0.017 min\(^{-1}\) nM\(^{-1}\) ) and dissociation (k\(_1\) = 0.017 min\(^{-1}\) ) kinetics, the half-life of dissociation being 41 min at 37°C. The kinetie K\(_D\) value amounted to 1.00 nM. M\(_1\) affinities for pirenzepine, methoctramine. hexahydro-sila-difenidol and p-fluoro-hexahydro-sila-difenidol detennined in competition experiments were similar to those found in functional studies with MI receptors in rabbit isolated vas deferens. The binding assay was used to deterriline the affinities of the (R) and (S) enantiomers of tertiary (trihexyphenidyl, hexahydro-difenidol. hexbutinol, p-fluoro-hexbutinol) and quatemary musearlnie antagonists (trihexyphenidyl methiodide. hexbutinol methiodide). Comparison of results obtained with the rabbit vas deferens suggested that the ionic environment may influence the affinities.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{TackePikiesWiesenbergeretal.1994,
  author    = {Tacke, Reinhold and Pikies, J. and Wiesenberger, F. and Ernst, L. and Schomburg, D. and Waelbroeck, M. and Christophe, J. and Lambrecht, G. and Gross, J. and Mutschler, E.},
  title     = {Sila-biperiden und endo-Sila-biperiden: Synthesen, Kristallstrukturen und antimuscarinische Eigenschaften},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64303},
  year      = {1994},
  abstract  = {Starting from trichloro(vinyl)silane (Cl\(_3\)SiCH=CH\(_2\)), the musearinic antagonists sila-biperiden [rac-(SiRS,C2SR>-ao-2] and endosila- biperiden [rac-(SiRS,C2SR)-endo-2] were prepared by a seven-step synthesis. Both silanols are configurationally stableininert organic solvents but undergo slow epimerization in aqueous solution (pH 7.4, 32°C) by inversion of the configuration at the silicon atom. The relative configurations of sila-biperiden and endo-sila-biperiden were detennined by single-crystal X-ray diffraction. Both compounds form intennolecular 0-H · · · N hydrogen bonds in the crystal leading to the fonnation of centrosymmetric dimers (sila-biperiden) and infinite chains (endo-sila-biperiden), respectively. Sila-biperiden is a silicon analogue (C/Si exchange) of the antiparkinsonian drug biperiden [rac-(CRS/C2SR}-exo-1]. In functional phannacological experiments, as well as in radioligand competition studies, biperiden, sila-biperiden and endo-sila-biperiden behaved as simple competitive antagonists at muscarinic Ml-, M2-, M3- and M4-receptors. The three compounds displayed the highest affinity for Ml-receptors (pA\(_2\) values: 8.72-8.80; pK\(_i\) values: 8.8-9.1), intermediate affinity for M4- and M3-receptors, and lowest affinity for M2-receptors (pA\(_2\) values: 7.57-7.79; pK\(_i\) values: 7.7-7.8). The affinity profile (Ml >. M4 > M3 > M2) of biperiden, sila-biperiden and endo-sila-biperiden is qualitatively similar to that of the M1-selective muscarinic antagonist pirenzepine. The antimuscarinic properlies of the C/Si analogues biperiden and sila-biperiden are almost identical.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{FeifelWagnerRoederStrohmannetal.1990,
  author    = {Feifel, R. and Wagner-R{\"o}der, M. and Strohmann, C. and Tacke, Reinhold and Waelbroeck, M. and Christophe, J. and Mutschler, E. and Lambrecht, G.},
  title     = {Stereoselective inhibition of muscarinic receptor subtypes by the enantiomers of hexahydro-difenidol and acetylenic analogues},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64002},
  year      = {1990},
  abstract  = {1 Tbc affinities of the (R)- and (S)-enantiomers of hexahydro-difenidol (1) and its acetylenie analogues hexbutinol (2), hexbutinol methiodide (3) and p-fluoro-hexbutinol (4) (stereochemieal purity > 99.8\%) for musearlnie receptors in rabbit vas deferens (M1), guinea-pig atria (M2) and guinea-pig ileum (M3) were measured by dose-ratio experiments. 2 The (R)-enantiomers consistently showed higher aßinities than the (S)-isomers. The stereosclectivity ratios [(R)/(S)] wcrc greatest with thc enantiomers of 1 (vas deferens: 550; ilcum: 191; atria: 17) and least with thosc ofthc p-Fluoro-analogue 4 (vas defercns: 34; ileum: 8.5; atria: 1.7). 3 The enantiomerie potency ratios for compounds 1-4 were highest in rabbit vas deferens, intermediate in guinea-pig ileum and much less in guinea-pig atria. Thus, these ratios may serve as a predietor of muscarinic receptor subtype identity. 4 (S)-p-Fluoro-hexbutinol [(S)-4] showed a novel receptor selectivity profile with preference for M\(_3\) receptors: M\(_3\) > M\(_2\) \(\geq\) M\(_1\)• 5 These results do not conform to Pfeiffer's rule that aetivity differences between enantiomers are greater with more potent compounds.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{WaelbroeckCamusTastenoyetal.1992,
  author    = {Waelbroeck, M. and Camus, J. and Tastenoy, M. and Mutschler, E. and Strohmann, C. and Tacke, Reinhold and Schjelderup, L. and Aasen, A. and Lambrecht, G. and Christophe, J.},
  title     = {Stereoselective interaction of procyclidine, hexahydro-difenidol, hexbutinol and oxyphencyclimine, and of related antagonists, with four muscarinic receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64237},
  year      = {1992},
  abstract  = {Wc invcstigatcd thc binding properlies of thc (R)- and (Sl-cnantiomcrs of thc muscarinic antagonists trihcxyphcnidyl, procyclidinc, hcxahydro-difcnidol. p-fluoro-hcxahydro-difcnidol. hcxbutinol, p-fluoro-hcxbutinnl. and thcir corrcsponding methiodidcs at muscarinic M\(_1\), M\(_2\)• M\(_3\) and M\(_4\) receptor subtypes. In addition. binding properlies of thc (R)- and (S)-cnantiomcrs of oxyphcncycliminc wcrc studicd. The {R)- cnantiomcrs (cutomcrs} of all the compounds had a grcatcr affinity than the (S)-isomcrs for thc four muscarinic rcccptor subtypcs. Thc binding pattcrns of thc (R)- and (S)-enantiomers wcrc gcncrally different. We did not obscrvc any gcncral corrclation hctwccn thc potcncy of thc high-affinity enantiomer and Lhc affinity ratio (cudismic ratio) of the two cnantiomcrs. Thc rcsuhs arc discusscd in tcrms of a 'four suhsitcs' binding modcl.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{WaelbroeckCamusTastenoyetal.1991,
  author    = {Waelbroeck, M. and Camus, J. and Tastenoy, M. and Mutschler, E. and Strohmann, C. and Tacke, Reinhold and Lambrecht, G. and Christophe, J.},
  title     = {Stereoselectivity of (R)- and (S)-hexahydro-difenidol binding to neuroblastoma M\(_1\), cardiac M\(_2\), pancreatic M\(_3\), and striatum M\(_4\) muscarinic receptors},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64135},
  year      = {1991},
  abstract  = {(R)-Hexahydro-difenidol has a higher affinity for M\(_1\) receptors in NB-OK 1 cells, pancreas M\(_3\) and striatum M\(_4\) receptors (pKi 7.9 to 8.3) than for cardiac M2 receptors (pKi 7 .0). (8)-Hexahydro-difenidol, by contrast, is nonselective (pKi 5.8 to 6.1). Our goal in the present study was to evaluate the importance ofthe hydrophobic phenyl, and cyclohexyl rings of hexahydro-difenidol for the stereoselectivity and reeeptor selectivity of hexahydro-difenidol binding to the four muscarinic receptors. Our results indieated that replacement of the phenyl ring of hexahydro-difenidol by a cyclohexyl group <~ dicyclidol) and ofthe cyclohexyl ring by a phenyl moiety <~ difenidol) indueed a !arge (4- to 80-fold) decrease in binding affinity for all musearlnie receptors. Difenidol had a signifieant preference for M\(_1\) , M\(_3\) , and M\(_4\) over M\(_2\) receptors; dicyclidol, by eontrast, had a greater affinity for M\(_1\) and M\(_4\) than for M\(_2\) and M\(_3\) receptors. The binding free energy deerease due to replacement ofthe phenyl and the cyelohexyl groups of(R)-hexahydro-difenidol by, respectively, a eyclohexyl and a phenyl moiety was almostadditive in the ease of M\(_4\) (striatum) binding sites. In the ease ofthe cardiac M\(_2\), pancreatic M\(_3\) , or NB-OK 1 M\(_1\) receptors the respective binding free energies were not eompletely additive. These results suggest that the four (R)-hexahydro-difenidol ''binding moieties" (phenyl, cyclohexyl, hydroxy, and protonated amino group) cannot simultaneously form optimal interaetions with the M\(_1\), M\(_2\), and M\(_3\) muscarinic receptors. When eaeh of the hydrophobic groups is modified, the position of the whole molecule, relative to the four subsites, was changed to allow an optimal overall interaction with the musearlnie receptor.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{WaelbroeckCamusTastenoyetal.1990,
  author    = {Waelbroeck, M. and Camus, J. and Tastenoy, M. and Lambrecht, G. and Mutschler, E. and Tacke, Reinhold and Christophe, J.},
  title     = {Stereoselectivity of procyclidine binding to muscarinic receptor subtypes M\(_1\), M\(_2\) and M\(_4\)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64034},
  year      = {1990},
  abstract  = {The goals of the present study were: (1) to investigate thc binding properlies oi (R)- and (S)-procyclidine and two aehiral derivatives of muscarinic M\(_1\)• M\(_2\) and M\(_4\) receptor subtypes and (2) to identify the interaetions which allow these receptors to diseriminate between the two stereoisomers. (R)-Procyclidine showed a higher affinity for human neuroblastoma NB-OK 1 muscarinie M\(_1\) and rat striatum musearinie M\(_4\) receptors. a~ compared to rat cardiac M\(_2\) receptors. (S)-Procyclidine had a 130-iold lower affinity than (R)-procyclidine for M\(_1\) and M\(_4\) receptors. and a 40-fold lower affinity for M\(_2\) receptors. Pyrrinol. the aehiral diphenyl derivative with the eyclohexyl g.roup of (S}-procyclidine replaeed by a phenyl group, has an eight-fold lower affinity for M\(_1\) and M\(_4\) receptors. as eompared to (R)-procyclidine, and a three-fold lower affinity for M\(_2\) receptors. Hexahydro-procyclidine. the eorresponding achiral dicyclohexyl compound, had a 10- to 20-fold lower affinity than (R)-procyclidine for the three reeeptors. The inerease in binding free energy, which is observed when the phenyl and eyclohexyl groups of procyelidine are separately replaeed by cyclohexyJ and phenyl groups, respectively. was additive in the ease of M\(_1\)• M\(_2\) and M\(_4\) receptcrs. This indicates that the musearinic reeeptor s!ereoseleetivity was based on the eoexistence of two binding sites, one preferring a phenylrather than eyclohexyl group and the seeond preferring a cyclohexyl rather than a phenyl group. In addition. there were aiso binding sites for the hydroxy moiety and the protonated amino group of the ligands. The greater affinity and stereoselectivity of M\(_1\) and M\(_4\) muscarinic receptors for (R)-procyelidine reflected the better fit of the eyclohexyl group of (R)-procyclidine to the subsite of M\(_1\) and M\(_4\) as compared to M\(_2\) receptors.},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@article{TackeLinohRafeineretal.1989,
  author    = {Tacke, Reinhold and Linoh, H. and Rafeiner, K. and Lambrecht, G. and Mutschler, E.},
  title     = {Synthese und Eigenschaften des selektiven Antimuscarinikums Sila-Hexocyclium-methylsulfat},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63921},
  year      = {1989},
  abstract  = {Sila-Hexocyclium-methylsulfat (7b), ein Silicium-Analogon des therapeutisch eingesetzten Antimuscarinileums Hexocyclium-methylsulfat (7a), wurde durch eine sechsstufige Synthese - ausgehend von (CH\(_3\)0)\(_3\)SiCH\(_2\)Cl - dargestellt (Gesamtausbeute 16\%). Außerdem wurden die hiervon abzuleitende freie Base 9b (f{\"u}nfstufige Synthese, ausgehend von (CH\(_3\)0)\(_3\)SiCH\(_2\)O; Gesamtausbeute 29\%) und das strukturverwandte (Aminomethyl)silanol 13 (dreistufige Synthese, ausgehend von cyclo-C\(_6\)H\(_{11}\)(C\(_6\)H\(_5\))Si(OCH\(_3\))CH\(_2\)Cl, Gesamtausbeute 46\$) synthetisiert. 7b ist ein hochwirksames und selektives Antimuscarinikum, das in der experimentellen Pharmakologie aufgrund seines bemerkenswerten Selektivit{\"a}tsprofils zur Klassifizierung von Subtypen muscarinischer Rezeptoren eingesetzt wird.},
  subject      = {Anorganische Chemie},
  language  = {de}
}
@article{TackeLinohZilchetal.1985,
  author    = {Tacke, Reinhold and Linoh, H. and Zilch, H. and Wess, J. and Moser, U. and Mutschler, E. and Lambrecht, G.},
  title     = {Synthese und Eigenschaften des selektiven Antimuskarinikums Cyclohexylphenyl(3-piperidinopropyl)silanol},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63798},
  year      = {1985},
  abstract  = {Die Synthese des selektiven Antimuskarinikums Cyclohexylpheny\{3-piperidinopropyl)sila· nol (1 b) wird beschrieben. 1 b wurde - ausgehend von (3·Chlorpropyl)trimethoxysilan - durch eine vierstufige Reaktionsfolge erhalten und als Hydrochlorid 2b mit einer Gesamtausbeute von etwa 45°/o isoliert. - 1 b ist aufgrund seiner großen pharmakologischen Se· lektivit{\"a}t zu einer Standardsubstanz in der experimentellen Pharmakologie bei der Differenzierung von Muskarinrezeptoren geworden.},
  subject      = {Anorganische Chemie},
  language  = {de}
}
@article{TackeRafeinerStrohmannetal.1989,
  author    = {Tacke, Reinhold and Rafeiner, K. and Strohmann, C. and Mutschler, E. and Lambrecht, G.},
  title     = {Synthesis of the selective antimuscarinic agent 4-{[cyclohexylhydroxy(2-methoxyphenyl)silyl]methyl}-1,1-dimethylpiperazinium methyl sulfate (o-methoxy-sila-hexocyclium methyl sulfate)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63930},
  year      = {1989},
  abstract  = {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 omethoxy derivative of sila-hexocyclium methyl sulfate, which represents one of the tools currently used in experimental pharmacology for the subclassification of muscarinic receptors. The omethoxy derivative, the pharmacological profile of which differs substantially from tbat of the nonmethoxy compound, is also recommended as a tool for the investigation of muscarinic receptor heterogeneity.},
  subject      = {Anorganische Chemie},
  language  = {en}
}