@article{JaiswalLambrechtMutschleretal.1991, author = {Jaiswal, Neelam and Lambrecht, G{\"u}nter and Mutschler, Ernst and Tacke, Reinhold and Malik, Kafait U.}, title = {Pharmacological characterization of the vascular muscarinic receptors mediating relaxation and contraction in rabbit aorta}, series = {Journal of Pharmacology and Experimental Therapeutics}, volume = {258}, journal = {Journal of Pharmacology and Experimental Therapeutics}, number = {3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-128358}, pages = {842-850}, year = {1991}, abstract = {Studies were performed in the rabbit aortic rings, precontracted with norepinephrine, to determine the subtype(s) of muscarinic receptors involved in endothelium-dependent relaxation and contraction in the absence of endothelium elicited by cholinergic stimuli. Acetylcholine (ACh) and arecaidine propargyl ester (APE), a M2 and M3 agonist, produced a dose-dependent relaxation and contraction in endothelium-intact and endothelium-denuded rabbit aortic rings, respectively. Both of these responses were blocked by the muscarinic receptor antagonist atropine. M1 selective agonist McN-A-343 [4-[N-(3-chlorophenyl)carbamoyloxy]-2-butinyltrimethylammonium+ ++ chloride] did not produce any effect on the tone of precontracted aortic rings. ACh- and APE-induced relaxation in aortic rings with intact endothelium was selectively blocked by M3 receptor antagonists hexahydrosila-difenidol and p-fluoro-hexahydro-sila-difenidol (pA2 of 7.84 and 7.18) but not by M1 antagonist pirenzepine or M2 receptor antagonists AF-DX 116 [11-(2-[(diethylamino)methyl]- 1-piperidinyl]acetyl)-5, 11-dihydro-6H-pyrido-[2,3-b][1,4]-benzo-diazepin-6-one] and methoctramine. ACh- and APE-induced contraction was inhibited by M2 receptor antagonists AF-DX 116 and methoctramine (pA2 of 7.11 and 6.71) but not by pirenzepine, hexahydro-sila-difenidol or p-fluoro-hexahydro-sila-difenidol. ACh- and APE-induced relaxation or contraction were not altered by nicotinic receptor antagonist hexamethonium or cyclooxygenase inhibitor indomethacin. These data suggest that relaxation elicited by cholinergic stimulin in endothelium-intact aortic rings is mediated via release of endothelium-derived relaxing factor consequent to activation of M3 receptors located on endothelial cells, whereas the contraction in aortic rings denuded of their endothelium is mediated via stimulation of M2 receptors located on smooth muscle cells.}, language = {en} } @article{TackeWiesenberger1991, author = {Tacke, Reinhold and Wiesenberger, Frank}, title = {(Acetoxymethyl)methylphenylgerman: Synthese, thermisches Verhalten und olfaktorische Eigenschaften}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-86927}, year = {1991}, abstract = {No abstract available.}, subject = {Chemische Synthese}, language = {de} } @article{TackeMahnerStrohmannetal.1991, author = {Tacke, Reinhold and Mahner, K. and Strohmann, C. and Forth, B. and Mutschler, E. and Friebe, T. and Lambrecht, G.}, title = {Cyclohexyl(4-fluorophenyl)(3-piperidinopropyl)silanol (p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD) and derivatives: synthesis and antimuscarinic properties}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64162}, year = {1991}, abstract = {Four different syntheses of the potent and selective muscanruc antagonist cyclohexyl( 4- fluorophenyl)(3-piperidinopropyl)silanol ( p-fluoro-hexahydro-sila-difenidol, p-F-HHSiD (2b); isolated as hydrochloride 2b· HCl) are described (starting materials: (CH\(_3\)O)\(_2\)SiCH\(_2\)CH\(_2\)CH\(_2\)Cl and Si(OCH\(_3\))\(_4\) ). In addition, the synthesis of the corresponding carbon analogue p-fluoro-hexahydro-difenidol ( p-F-HHD (2a); isolated as 2a· HCI) and the syntheses of three p-F-HHSiD derivatives (3-5), with a modified cyclic amino group, are reported (3: piperidinojpyrrolidino exchange, isolated as 3· HCI; 4: piperidinoj hexamethylenimino exchange, isolated as 4 · HCl; 5: quaternization of 2b with methyl iodide). The chiral compounds 2a, 2b, 3, 4 and 5 were prepared as racemates. In functional pharmacological studies, 3-5 behaved as simple competitive antagonists at musearlnie Ml receptors in rabbit vas deferens, M2 receptors in guinea-pig atria, and M3 receptors in guinea-pig ileal smooth rnuscle. The pyrrolidino (3) and hexamethylenimino (4) analogues of the parent drug p-F-HHSiD (2b) displayed the highest affinity for Ml and M3 receptors (pA\(_2\) values: 7.0-7.4) but exhibited lower affinity for cardiac M2 receptors (pA\(_2\) : 5.9 and 6.0). Their affinity profile (Ml- M3 > M2) is different from that of p-F-HHSiD (2b) (M3 > Ml > M2), but qualitatively very similar tothat of p-F-HHD (2a). The methiodide 5 exhibited the highest affinity for Ml receptors (pA\(_2\) : 8.5) but lower affinity for M2 and M3 receptors by factors of 5.6 and 3.6, respectively.}, subject = {Anorganische Chemie}, language = {en} } @article{HengelsbergTackeFritscheetal.1991, author = {Hengelsberg, H. and Tacke, Reinhold and Fritsche, K. and Syldatk, C. and Wagner, F.}, title = {Synthesis and enantioselective enzymatic hydrolysis of rac-dimethylphenyl[1-(phenylacetamido)- ethyl]silane}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64153}, year = {1991}, abstract = {Racemic dimethylphenyl(l-(phenylacetamido)ethyl)silane [rac-5) has been made by a four-step synthesis starting from (chloromethyl)dimethylphenylsilane [PhMe\(_2\)SiCH2Cl (1) ~ PhMe\(_2\)SiCH(Cl)Me (rac-2) - PhMe\(_2\)SiCH(l)Me (rac-3) - PhMe2SiCH(NH2)Me (rac-4) ~ PhMe\(_2\)SiCH[N(H)C(O)CH\(_2\)Ph]Me ( rac-5); total yield 41\% ). Enantioselective enzymatic hydrolysis of rac-5, catalyzed by immobilized penicillin G acylase (E.C. 3.5.1.11) from Escherichia coli 5K (pHM 12), gave (R)-(1- aminoethyl)dimethylphenylsilane [( R )-4] in 40\% yield with an enantiomeric purity of 92\% ee.}, 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{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.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 = {Binding affinities of hexahydro-difenidol and hexahydro-sila-difenidol analogues at four muscarinic receptor subtypes: constitutional and stereochemical aspects}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64128}, year = {1991}, abstract = {Hexahydro-sila-difenidoJ and eight analogues behaved as simple cumpetitive inhibitors of eHJN·methyl·scopoJamine binding to homogenates frorn human neuroblastoma NB-OK 1 cells (M\(_1\) sites), rat heart (M\(_2\) sites), rat pancreas (M\(_3\) sites), and rat striatum 'B' sites (M\(_4\) sites). Pyrrolidino- and hexamethyleneimino analogues showed the same sekctivity profile as the parent compound. Hexahydro-sila-difenidol methiodide and the methiodide of p-fluoro-hexahydro·sila-difenidol had a f{\"u}gher affinity but a lower selectivity than the tertiary amines. Compounds containing a p·methoxy, p-chJoro or p-fluoro substituent in the phenyl ring of hexahydro-sila-difenidol showed a qualitative)y similar selectivity profile as the parent compound (i.e., M\(_1\)= M\(_3\) = M\(_4\) >M\(_2\) ), but up to 16-fold lower affinities. o-Methoxy-hexahydro-sila-difenidol has a lower affinity than hexahydro-sila-difeni.:!o! at the four binding sites. lts selectivity profile (M\(_4\) > M\(_1\), M\(_3\) > M\(_2\) ) was different from hexahydro-sila-difenidol. Replacement of the centrat silicon atom of hexahydro-sila-difenidol, p-fluoro-hexahydro-sila-difenidol and thdr quatemary (N-methylated) analogues by a carbon atom did not change their binding affinities significantly. The iour muscarinic receptors showed a higher affinity for the (R)- than for the (S)-enantiomers of hexahydro-difenidol, p-fluorohexahydro-difenidol and their methiodides. The stereoselectivity varied depending on the receptor subtype and drug considered.}, subject = {Anorganische Chemie}, language = {en} } @article{DoerjeWessLambrechtetal.1991, author = {D{\"o}rje, F. and Wess, J. and Lambrecht, G. and Tacke, Reinhold and Mutschler, E. and Brann, M. R.}, title = {Antagonist binding profiles of five cloned human muscarinic receptor subtypes}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64113}, year = {1991}, abstract = {A variety of muscarinic antagonists are currently used as tools to pharmacologically subclassify muscarinic receptors into M\(_1\), M\(_2\) and M\(_3\) subtypes. ln the present study I we have determined the affinity proflies of several of these antagonists at five cloned human muscarinic receptors (m1-m5) stably expressed in Chinesehamster ovary cells (CHO-K1). At all five receptorsl the (R)-enantiomers of trihexyphenidyl and hexbutinol displayed considerably higher affinities (up to 525-fold) than their corresponding (S)-isomers. The stereoselectivity ratios [inhibition constant( S)/inhibition constant(R)] for both pairs of enantiomers were lowest at m2 receptors, suggesting that less stringent configurational demands are made by this receptor subtype. The "M\(_1\)-selective" antagonist (R)-trihexyphenidyl displayed high affinities for m1 and m4 receptors. The "M\(_2\)-selective" antagonists himbacinel (±}-5, 11-dihydro-11-1[(2-[(dipropylamino)methyl]-1- piperidinyllethyl)amino]carbonyii-6H-pyrido(213-b)(1 ~4)benzodiazepine- 6-one (AF-DX 384)1 11-(14-[4-(diethylamino)butyl)-1-piperidinyll acetyl)-5~ 11-dihydro-6H-pyrido(2~3-b) (1~4)benzodiazepine-6-one (AQ-RA 741) and (+K11-(12-[(diethylamino)methyl]-1-piperidinyll acetyl)-5~ 11-di-hydro-6H-pyrido(2~3-b)(1,4)benzodiazepine-6-one (AF-OX 250; the (+)-enantiomer of AF-DX 116] exhibited high affinities for m2 and m41 intermediate affinities for m1 and m3 and low affinities for m5 receptors. This selectivity profile was most prominent for AQ-RA 7 41 I which displayed 195- and 129-fold higher affinities for m2 and m4 receptors than for mS receptors. The "M\(_3\)-selective" antagonist (±)-p-fluoro-hexahydro-sila-difenidol hydrochloride (pFHHsiD) exhibited high affinity for m1 I m3 and m4 receptors. 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) bound with up to 7 -fold higher affinities to m1 I m31 m4 and m5 receptors than to m2 receptors. Although none of the tested antagonists showed more than 2-fold selectivity for one subtype over all other subtypes, each receptor displayed a unique antagonist binding profile.}, subject = {Anorganische Chemie}, language = {en} } @article{TackeBrakmannWuttkeetal.1991, author = {Tacke, Reinhold and Brakmann, S. and Wuttke, F. and Fooladi, J. and Syldatk, C. and Schomburg, D.}, title = {Stereoselective microbial reduction of racemic acetyl(t-butyl)methylphenylsilane by Trigonopsis variabilis (DSM 70714) and Corynebacterium dioxydans (ATCC 21766)}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64109}, year = {1991}, abstract = {(SiR,CR)- and (SiS,CR)-t-butyl(l-hydroxyethyl)methylphenylsilane [(SiR,CR)-2 and (SiS,CR)-3] have been prepared by (R)-selective microbial rcduction of racemic acetyl(t-butyl)methylphenylsilane (rac-1) using resting free cells of the yeast Trigonopsis variabilis (DSM 70714) or the bacterium Corynebacterium dioxydans (ATCC 21766). The biotransfonnations were carried out on a 10 g scale. Afterseparation by column chromatography on silica gel, the optically active diastereomers (SiR,CR)-2 and (SiS,CR)-3 produccd by T. variabilis were obtained in good yields [74\% ((SiR,CR)-2). 78\% ((SiS,CR)-3)]. The products obtained from the reduction with C. dioxydans were isolated in significantly lower yields [20\% ((SiR,CR)-2), 20\% ((SiS,CR)-3)]; reaction conditions not optimized). Both bioconversions gave products with high enantiomeric purities (T. variabilis: 91\% ee ((SiR,CR)-2), 96\% ee ((SiS,CR)-3); C. dioxydons: ~ 991 ee ((SiR,CR)-l), ~ 99\% ee ((SiS,CR)-3)). To throw light on the stereochemical aspects of these biotransfonnations, an X-ray diffraction study was carried out on the 3,5-dinitrobenzoate of rac-(SiR,CS/SiS,CR)-3. In addition, 1H NMR spectroscopic stereochemical correlation studies were performed with the (S)-MTPA esters derived from (SiR,CR)-l, (SiS,CR)-3, rac-(SiR,CRjSiS,CS)-2 and rac-(SiR,CSjSiS,CR)-3 [rac-(SiR,CR/ SiS,CS)-2 and rac-(SiR,CS/SiS,CR)-3 were obtained by reduction of rac-1 with LiAIH\(_4\) in diethylether, followed by chromatographic separation of the diastereomers on silica gel]. These stereochemical studies allowed assignment of the absolute configurations and enantiomeric purities of the biotransformation products.}, subject = {Anorganische Chemie}, language = {en} } @article{StrohmannTackeMatternetal.1991, author = {Strohmann, C. and Tacke, Reinhold and Mattern, G. and Kuhs, W. F.}, title = {Bis(2,3-naphthalindiolato)[2-(pyrrolidinio)ethyl]silicat: Synthese und strukturelle Charakterisierung eines zwitterionischen \(\lambda_5\)-Spirosilicates}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-64095}, year = {1991}, abstract = {The zwi tterionic spirocyclic bis(2,3-naphthalenediolato )[2-(pyrrolidinio )ethyl]silicate [ ( C\(_{10}\)H\(_6\)O\(_2\)-SiCH\(_2\)CH\(_2\)(H)NC\(_4\)H\(_8\), 3 was synthesized and its structure characterized (single crystal X-ray structural analysis; \(^1\)H, \(^{13}\)C and \(^{29}\)Si NMR studies of solutions in DMSO). 3 was obtained by reaction of cyclohexylmethoxyphenyl(2-pyrrolidinoethyl)silane [C\(_6\)H\(_{11}\)(CH\(_3\)O)Si(C\(_6\)H\(_5\))CH\(_2\)CH\(_2\) NC\(_4\)H\(_8\), 4] with 2,3-dihydroxynaphthalene [C\(_{10}\)H\(_6\)(OH)\(_2\)] in acetonitrile at room temperature (isolated as 3·CH\(_3\)CN, yield 81 \%). The formation of 3 involves two unusual Si-C cleavage reactions (cleavage of Si-C\(_6\)H\(_5\) and Si-C\(_6\)H\(_{11}\) under mild reaction conditions). In addition, 3 was prepared by reaction of 2,3-dihydroxynaphthalene with dimethoxyphenyl(2-pyrrolidinoethyl)silane [C\(_6\)H\(_5\) (CH\(_3\)O)\(_2\)SiCH\(_2\)CH\(_2\)NC\(_4\)H\(_8\) , 5] and trimethoxy( 2-pyrrolidinoethyl)silane [(CH\(_3\)O)\(_3\)SiCH\(_2\)CH\(_2\)NC\(_4\)H\(_8\), 6], respectively (isolated as 3·CH\(_3\)CN; yields 83 and 86\%, respectively). 3·CH\(_3\)CN crystallizes in the space group Pbca with a = 8.877(2) A. b-= 22.823(4) {\"A}, c""" 24.597(4) A, and Z = 8 (R- 0.0592, Rw = 0.0529). The pentacoordinated Si atom of 3·CH\(_3\)CN is surrounded by its ligands in a nearly ideal square-pyramidal fashion (four basal 0 atoms and one apical C atom). The CH3CN molecule does not coordinate to the Si atom.}, subject = {Anorganische Chemie}, language = {de} }