@article{SheldrickLinohTackeetal.1985,
  author    = {Sheldrick, W. S. and Linoh, H. and Tacke, Reinhold and Lambrecht, G. and Moser, U. and Mutschler, E.},
  title     = {Crystal and molecular structures of the (R)-enantiomer and the racemate of the antimuscarinic agent (cyclohexyl)phenyl[2-(pyrrolidin-1-yl)ethyl]silanol (sila-procyclidine)},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63776},
  year      = {1985},
  abstract  = {The crystal structures of the (R)-enantiomer (2b) and the racemate (1 b) of (cyclohexyl)phenyl[2- (pyrrolidin-1-yl)ethyl]silanol (sila--procyclidine) have been determined by X -ray structural analysis. The absolute configuration of (2b) was established. (2b) crystallizes in the orthorhombic space group P2\(_1\)2\(_1\)2\(_1\), with a = 15.221 (1 ), b = 17.967(1 ), c = 6.463(1) A, and Z = 4. (1 b) crystallizes in the monoclinic space group P2\(_1\)/c, with a = 6.441 (1 ), b = 17.1 82(7), c = 16.707(4) A, ß = 1 03.86(2r, and Z = 4. The structures were refined to respective R factors of 0.044 and 0.058. The molecular conformation of sila-procyclidine is identical in the two different structures. lntermolecular 0-H • • • N hydrogen bonding is observed in both crystallattices.ln (1 b) (R)- and (S)-configurated molecules form centrosymmetric dimers, in (2b) the (R)-configurated molecules are linked into infinite chains parallel to the c axis. The (R)-configurated sila--procyclidine (2b) has higher affinity for ileal and atrial muscarinic receptors of the guinea pig than the (S)-configurated enantiomer (3b).},
  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{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{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}
}
@article{WaelbroeckTastenoyCamusetal.1989,
  author    = {Waelbroeck, M. and Tastenoy, M. and Camus, J. and Christophe, J. and Strohmann, C. and Linoh, H. and Zilch, H. and Tacke, Reinhold and Mutschler, E. and Lambrecht, G.},
  title     = {Binding and functional properties of antimuscarinics of the hexocyclium/sila-hexocyclium and hexahydro-diphenidol/hexahydro-sila-diphenidol type to muscarinic receptor subtypes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63944},
  year      = {1989},
  abstract  = {l In an attempt to assess the structural requirements for the musearlnie receptor selectivity of hexahydro-diphenidol (hexahydro-difenidol) and hexahydro-sila-diphenidol (hexahydro-sila-difenidol), a serles of structurally related C/Si pairs were investigated, along with atropine, pirenzepine and methoctramine, for their binding affinities in NB-OK 1 cells as well as in rat heart and pancreas. 2 The action of these antagonists at musearlnie receptors mediating negative inotropic responses in guinea-pig atrla and ileal contractions has also been assessed. 3 Antagonist binding data indicated that NB-OK 1 cells (M\(_1\) type) as weil as rat heart (cardiac type) and pancreas (glandularjsmooth muscle type) possess different muscarinic receptor subtypes. 4 A highly significant correlation was found between the binding affinities of the antagonists to muscarinic receptors in rat heart and pancreas, respectively, and the affinities to muscarinic receptors in guinea-pig atria and ileum. This implies that the musearlnie binding sites in rat heart and the receptors in guinea-pig atrla are essentially similar, but different from those in pancreas and ileum. 5 The antimuscarinic potency of hexahydro-diphenidol and hexahydro-sila-diphenidol at the three subtypes was inftuenced differently by structural modifications (e.g. quaternization). Different selectivity profiles for the antagonists were obtained, which makes these compounds useful tools to investigate further muscarinic receptor heterogeneity. lndeed, the tertiary analogues hexahydrodiphenidol (HHD) and hexahydro-sila-diphenidol (HHSiD) bad an M\(_1\) = glandularjsmooth muscle > cardiac selectivity profile, whereas the quaternary analogues HHD methiodide and HHSiD methiodide were M\(_1\) preferring (M\(_1\) > glandularjsmooth muscle, cardiac).},
  subject      = {Anorganische Chemie},
  language  = {en}
}
@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{LambrechtFeifelWagnerRoederetal.1989,
  author    = {Lambrecht, G. and Feifel, R. and Wagner-R{\"o}der, M. and Strohmann, C. and Zilch, H. and Tacke, Reinhold and Waelbroeck, M. and Christophe, J. and Boddeke, H. and Mutschler, E.},
  title     = {Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-63979},
  year      = {1989},
  abstract  = {In an attempt to assess the structural requirements of hexahydro-sila-difenidol for potency and selectivity, a series of analogues modified in the amino group and the phenyl ring were investigated for their affinity to muscarinic M1- (rabbit vas deferens), Mr (guinea-pig atria) and Mr (guinea-pig ileum) receptors. All compounds were competitive antagonists in the three tissues. Their affinities to the three muscarinic receptor subtypes differed by more than two orders of magnitude and the observed receptor selectivities were not associated with high affinity. The pyrrolidino and hexamethyleneimino analogues, compounds substituted in the phenylring with a methoxy group or a chlorine atom as weil as p-fluoro-hexahydro-difenidol displayed the same affinity profile as the parent compound, hexahydro-sila-difenidol: M1 = M3 > M2 • A different selectivity patternwas observed for p-fluoro-hexahydro-sila-difenidol: M3 > M1 > M2 • This compound exhibited its highest affinity for M3-receptors in guinea-pig ileum (pA 2 = 7.84), intermediate affinity for M1-receptors in rabbit vas deferens (pA 2 = 6.68) and lowest affinity for the Mrreceptors in guinea-pig atria (pA 2 = 6.01). This receptor selectivity profile of p-fluoro-hexahydro-sila-difenidol was confirmed in ganglia (M1), atria (M2 ) and ileum (M 3 ) of the rat. Furthermore, dose ratios obtained with either pirenzepine (Mt) or hexahydrosila- difenidol (M2 and M3) and the p-fluoro analogue used in combination suggested that the antagonism was additive, implying mutual competition with a single population of muscarinic receptor subtypes. These results indicate that p-fluoro-hexahydro-sila-difenidol represents a valuable tool for characterization of muscarinic receptor subtypes.},
  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{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}
}