TY - JOUR A1 - Tacke, Reinhold A1 - Rafeiner, K. A1 - Strohmann, C. A1 - Mutschler, E. A1 - Lambrecht, G. T1 - Synthesis of the selective antimuscarinic agent 4-{[cyclohexylhydroxy(2-methoxyphenyl)silyl]methyl}-1,1-dimethylpiperazinium methyl sulfate (o-methoxy-sila-hexocyclium methyl sulfate) N2 - 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. KW - Anorganische Chemie KW - o-methoxy-sila-hexocyclium KW - silahexocyclium KW - sila-drugs KW - antimuscarinics KW - muscarinic receptor subtypes Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63930 ER - TY - JOUR A1 - Waelbroeck, M. A1 - Tastenoy, M. A1 - Camus, J. A1 - Christophe, J. A1 - Strohmann, C. A1 - Linoh, H. A1 - Zilch, H. A1 - Tacke, Reinhold A1 - Mutschler, E. A1 - Lambrecht, G. T1 - Binding and functional properties of antimuscarinics of the hexocyclium/sila-hexocyclium and hexahydro-diphenidol/hexahydro-sila-diphenidol type to muscarinic receptor subtypes N2 - 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). KW - Anorganische Chemie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63944 ER - TY - JOUR A1 - Tacke, Reinhold A1 - Strohmann, C. A1 - Sarge, S. A1 - Cammenga, H. K. A1 - Schomburg, D. A1 - Mutschler, E. A1 - Lambrecht, G. T1 - Darstellung und Eigenschaften der Enantiomere des selektiven Antimuscarinikums 1-Cyclohexyl-1-phenyl-4-piperidino-1-butanol (Hexahydro-Difenidol) N2 - No abstract available KW - Anorganische Chemie KW - Difenidol KW - (R)- and (S)-hexahydro- / Antimuscarinic properties / Muscarinic receptor subtypes Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63950 ER - TY - JOUR A1 - Fritsche, K. A1 - Syldatk, C. A1 - Wagner, F. A1 - Hengelsberg, H. A1 - Tacke, Reinhold T1 - Enzymatic resolution of rac-1,1-dimethyl-1-sila-cyclohexan-2-ol by ester hydrolysis or transesterification using a crude lipase preparation of Candida cylindracea N2 - No abstract available KW - Anorganische Chemie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63967 ER - TY - JOUR A1 - Lambrecht, G. A1 - Feifel, R. A1 - Wagner-Röder, M. A1 - Strohmann, C. A1 - Zilch, H. A1 - Tacke, Reinhold A1 - Waelbroeck, M. A1 - Christophe, J. A1 - Boddeke, H. A1 - Mutschler, E. T1 - Affinity profiles of hexahydro-sila-difenidol analogues at muscarinic receptor subtypes N2 - 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. KW - Anorganische Chemie KW - Muscarinic receptor subtypes KW - Muscarinic M3selective antagonists KW - Hexahydro-sila-difenidol analogues Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63979 ER - TY - JOUR A1 - Kopp, R. A1 - Lambrecht, G. A1 - Mutschler, E. A1 - Moser, U. A1 - Tacke, Reinhold A1 - Pfeiffer, A. T1 - Human HT-29 colon carcinoma cells contain mucarinic M\(_3\) receptors coupled to phosphoinositide metabolism N2 - 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. KW - Anorganische Chemie KW - Muscarinic M3 receptor subtypes KW - HT-29 colon carcinoma cells KW - Phosphatidylinositol metabolism KW - AF-DX 116 Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-63989 ER - TY - JOUR A1 - Tacke, Reinhold A1 - Hengelsberg, H. A1 - Zilch, H. A1 - Stumpf, B. T1 - Enantioselective microbial reduction of 1,1-dimethyl-1-sila-cyclohexan-2-one with growing cells of the yeast Kloeckera corticis (ATCC 20109) N2 - (R)-1,1-Dimethyl-1-sila-cyclohexan-2-ol [(R)-2] was prepared by enantioselective microbial reduction of 1,1-dimethyl-1-sila-cyclohexan-2-one (1) with growing cells of the yeast Kloeckera corticis (ATCC 20109). At a substrate concentration of 0.5 g/1 (temperature 27° C, incubation time 16 h), (R}-2 was obtained on a preparative scale in 60% yield and with an enantiomeric purity of 92% ee. Repeated recrystallization of the biotransformation product from n-hexane raised the enantiomeric purity to 99% ee. KW - Anorganische Chemie Y1 - 1989 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-64010 ER -