TY - JOUR A1 - Waelbroeck, M. A1 - Camus, J. A1 - Tastenoy, M. A1 - Lambrecht, G. A1 - Mutschler, E. A1 - Kropfgans, M. A1 - Sperlich, J. A1 - Wiesenberger, F. A1 - Tacke, R. A1 - Christophe, J. T1 - Thermodynamics of antagonist binding to rat muscarinic \(M_2\) receptors: antimuscarinics of the pridinol, sila-pridinol, diphenidol and sila-diphenidol type JF - British Journal of Pharmacology N2 - 1 We studied the effect of temperature on the binding to rat heart \(M_2\) muscarinic receptors of antagonists related to the carbon/silicon pairs pridinol/sila-pridinol and diphenidol/sila-diphenidol (including three germanium compounds) and six structurally related pairs of enantiomers [(R)- and (S)-procyclidine, (R)- and (S)-trihexyphenidyl, (R)- and (S)-tricyclamol, (R)- and (S)-trihexyphenidyl methiodide, (R)- and (S)-hexahydro-diphenidol and (R)- and (S)-hexbutinol]. Binding affinities were determined in competition experiments using \([^3H]\)-N-methyl-scopolamine chloride as radioligand. The reference drugs were scopolamine and N-methyl-scopolamine bromide. 2 The affinity of the antagonists either increased or decreased with temperature, van 't Hoff plots were linear in the 278–310°K temperature range. Binding of all antagonists was entropy driven. Enthalpy changes varied from large negative values (down to \(−29 kJ mol^{−1}\)) to large positive values (up to \(+ 30 kJ mol^{−1}\)). 3 (R)-configurated drugs had a 10 to 100 fold greater affinity for \(M_2\) receptors than the corresponding (S)-enantiomers. Enthalpy and entropy changes of the respective enantiomers were different but no consistent pattern was observed. 4 When silanols \((R_3SiOH)\) were compared to carbinols \((R_3COH)\), the affinity increase caused by C/Si exchange varied between 3 and 10 fold for achiral drugs but was negligible in the case of chiral drugs. Silanols induced more favourable enthalpy and less favourable entropy changes than the corresponding carbinols when binding. Organogermanium compounds \((R_4Ge)\) when compared to their silicon counterparts (R4Si) showed no significant difference in affinity as well as in enthalpy and entropy changes. 5 Exchange of a cyclohexyl by a phenyl moiety was associated with an increase or a decrease in drug affinity (depending on the absolute configuration in the case of chiral drugs) and generally also with a more favourable enthalpy change and a less favourable entropy change of drug binding. 6 Replacement of a pyrrolidino by a piperidino group and increasing the length of the alkylene chain bridging the amino group and the central carbon or silicon atom were associated with either an increase or a decrease of entropy and enthalpy changes of drug binding. However, there was no clear correlation between these structural variations and the thermodynamic effects. 7 Taken together, these results suggest that hydrogen bond-forming OH groups and, to a lesser extent, polarizable phenyl groups contribute significantly to the thermodynamics of interactions between these classes of muscarinic antagonists and \(M_2\) muscarinic receptors. KW - entropy KW - binding KW - M2 muscarinic receptors KW - thermodynamics KW - van 't Hoff plot KW - enthalpy Y1 - 1993 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128439 VL - 109 IS - 2 ER - TY - JOUR A1 - Tacke, R. A1 - Strecker, M. A1 - Sheldrick, W. S. A1 - Heeg, E. A1 - Berndt, B. A1 - Knapstein, K. M. T1 - Sila-Pharmaka, 14. Mitt. Darstellung und Eigenschaften sowie Kristall-und Molekülstruktur von Sila-Difenidol JF - Zeitschrift für Naturforschung B N2 - Sila-difenidol (6b), a sila-analogue of the drug difenidol (6a), was synthesized according to Scheme 1. 6b and its new precursors 3 and 5 were characterized by their physical and chemical properties, and their structures confirmed by elementary analyses, 1H NMR and mass spectroscopy. 6 b crystallizes orthorhombic \(P2_12_12_1\) with a = 11.523(1), b = 14.366(4), c = 11.450(1) Å, Z = 4, \(D_{ber} = 1.14 gcm^{-3}\). The structure was refined to R = 0.050 for 1897 reflexions. A strong nearly linear intramolecular O-H···N hydrogen bond of 2.685 Å is observed. The anticholinergic, histaminolytic and musculotropic spasmolytic activities of 6 a and 6 b are reported. KW - sila-difenidol KW - syntheses KW - crystal structure KW - molecular structure KW - biological activity Y1 - 1979 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128391 VL - 34 IS - 9 ER - TY - JOUR A1 - Tacke, R. A1 - Bentlage, A. A1 - Sheldrick, W. S. A1 - Ernst, L. A1 - Towart, R. A1 - Stoepel, K. T1 - Sila-Pharmaka, 24. Mitt. [1]. Sila-Analoga von Nifedipin-ähnlichen 4-Aryl-2.6-dimethyl-1.4-dihydropyridin- 3.5-dicarbonsäure-dialkylestern, II. T1 - Sila-Drugs, 24th Communication [1]. Sila-Analogues of Nifedipine-Like Dialkyl 4-Aryl-2,6-dimethyl-1,4-dihydropyridine- 3,5-dicarboxylates, II. JF - Zeitschrift für Naturforschung B N2 - In the course of systematic studies on sila-substituted drugs the nifedipine-like 1.4-dihydropyridine derivatives 4a, 4b and 4c were prepared and investigated with respect to sila-substitution effects. By X-ray diffraction analyses 4a, 4b and 4c were found to be isostructural. The C/Si-analogues exhibit similar spasmolytic activities (in vitro, guinea pig ileum), comparable with that of nifedipine. However, the compounds differ substantially in their in vivo activity, as measured by the antihypertensive effect on the renal-hypertensive rat. The experimental results are discussed with respect to the carbon/silicon exchange. KW - sila-analogues of Nifedipine derivatives KW - X-ray KW - pharmacological activity KW - structure-activity relationships Y1 - 1982 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128381 VL - 37 IS - 4 ER - TY - JOUR A1 - Pfeiffer, A. A1 - Rochlitz, H. A1 - Noelke, B. A1 - Tacke, R. A1 - Moser, U. A1 - Mutschler, E. A1 - Lambrecht, G. T1 - Muscarinic receptors mediating acid secretion in isolated rat gastric parietal cells are of M3 type JF - Gastroenterology N2 - Five subtypes of muscarinic receptors have been identified by pharmacological and molecular biological methods. The muscarinic receptor subtype mediating acid secretion at the level of the parietal cell was unknown. Therefore, this study was performed to characterize muscarinic receptors on rat gastric parietal cells using the 3 subtype-selective antagonists hexahydrosiladifenidol and silahexocyclium, which have high affinity for glandular M3 subtypes, and AF-DX 116, which has high affinity to cardiac M2 receptors. The affinity of these antagonists was determined by radioligand binding experiments. In addition, their inhibitory potency on carbachol-stimulated inositol phosphate production was investigated. Inhibition of carbachol-stimulated aminopyrine uptake was used as an indirect measure of proton production. Both M3 antagonists, hexahydrosiladifenidol and silahexocyclium, had nanomolar affinities for parietal cell muscarinic receptors and potently antagonized inositol phosphate production with nanomolar Ki values. Silahexocyclium similarly antagonized aminopyrine accumulation while hexahydrosiladifenidol behaved as a noncompetitive antagonist. AF-DX 116 was a low-affinity ligand and a weak competitive antagonist at parietal-cell muscarinic receptors. It was concluded that muscarinic M3 receptors mediate acid secretion probably by activation of the phosphoinositide second messenger system in rat gastric parietal cells. KW - hexahydrosiladifenidol KW - muscarinic receptors KW - parasympatholytics KW - radioligand assay KW - parasympatholytics/pharmacology KW - gastric acid/secretion KW - animals KW - piperidines/pharmacology KW - piperazines/pharmacology KW - gastric/secretion parietal cells KW - muscarinic/physiology receptors KW - muscarinic/drug effects receptors KW - rats KW - piperidines KW - piperazines KW - silahexocyclium Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128337 VL - 98 IS - 1 ER - TY - JOUR A1 - Pfeiffer, A. A1 - Hanack, C. A1 - Kopp, R. A1 - Tacke, R. A1 - Moser, U. A1 - Mutschler, E. A1 - Lambrecht, G. A1 - Herawi, M. T1 - Human Gastric Mucosa Expresses Glandular M3 Subtype of Muscarinic Receptors JF - Digestive Diseases and Sciences N2 - Five subtypes of muscarinic receptors have been distinguished by pharmacological and molecular biological methods. This report characterizes the muscarinic subtype present in human gastric mucosa by radioligand binding studies. The receptor density was 27 ± 6 fmol/mg protein and the tritiated ligand N-methylscopolamine had an affinity of (Kn) 0.39 ± 0.08 nM (n = 11). The M1 receptor selective antagonist pirenzepine and the M2 receptor selective ligand AF-DX 116 had low affinities of 148 ± 32 nM (n = 13) and 4043 ± 1011 nM (n = 3) K n , respectively. The glandular M3 antagonists hexahydrosiladifenidol and silahexocyclium had high affinities ofKn 78 ± 23 nM (n = 5) and 5.6 ± 1.8 nM (n = 3). The agonist carbachol interacted with a single low-affinity site and binding was insensitive to modulation by guanine nucleotides. Antagonist and agonist binding studies thus showed an affinity profile typical of M3 receptors of the glandular type. KW - glandular M3 receptor KW - acid secretion KW - muscarinic receptor subtype KW - human gastric mucosa KW - stomach Y1 - 1990 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128286 VL - 35 IS - 12 ER - TY - JOUR A1 - Waelbroeck, M. A1 - Camus, J. A1 - Tastenoy, M. A1 - Feifel, R. A1 - Mutschler, E. A1 - Tacke, R. A1 - Strohmann, C. A1 - Rafeiner, K. A1 - Rodrigues de Miranda, J. F. A1 - Lambrecht, G. T1 - Binding and functional properties of hexocyclium and sila-hexocyclium derivatives to muscarinic receptor suhtypes JF - British Journal of Pharmacology N2 - 1 We have compared the binding properties of several hexocyclium and sila-hexocyclium derivatives to muscarinic Ml receptors (in rat brain, human neuroblastoma (NB-OK I) cells and calf superior cervical ganglia), rat heart M2 receptors, rat pancreas M3 receptors and M4 receptors in rat striatum, with their functional antimuscarinic properties in rabbit vas deferens (Ml/M4-like), guinea-pig atria (M2), and guinea-pig ileum (M3) muscarinic receptors. 2 Si la-substitution (C/Si exchange) of hexocyclium (~ sila-hexocyclium) and demethyl-hexocyclium (~demethyl-sila-hexocyclium) did not significantly affect their affinities for muscarinic receptors. By contrast, sila-substitution of demethoxy-hexocyclium increased its affinity 2 to 3 fold for all the muscarinic receptor subtypes studied. 3 The p-fluoro- and p-chloro-derivatives of sila-hexocyclium had lower affinities than the parent compound at the four receptor subtypes, in binding and pharmacological studies. 4 In binding studies, o-methoxy-sila-hexocyclium (Ml = M4 ~ M3 ~ M2) had a much lower affinity than sila-hexocyclium for the four receptor subtypes, and discriminated the receptor subtypes more poorly than sila-hexocyclium (Ml = M3> M4> M2)' This is in marked contrast with the very clear selectivity of demethoxy-sila-hexocyclium for the prejunctional MtlM4-like heteroreceptors in rabbit vas deferens. 5 The tertiary amines demethyl-hexocyclium, demethyl-sila-hexocyclium and demethyl-o-methoxy-silahexocyclium had 10 to 30 fold lower affinities than the corresponding quaternary ammonium derivatives. KW - Hexocyclium/sila-hexocyclium derivatives KW - o-methoxy-sila-hexocyclium KW - muscarinic receptor subtypes KW - structure/ affinity relationships KW - binding/functional correlations KW - muscarinic receptor antagonists Y1 - 1994 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-128265 VL - 112 ER -