Neuartige zwitterionische λ5-Spirosilicate: Synthese und Kristallstruktur von Bis[1,2-benzoldiolato(2-)][2-(dimethylammonio)phenyl]silicat sowie Synthese von Bis[2,3-naphthalindiolato(2-)][2-(dimethylammonio)phenyl]silicat-Hemiacetonitril-Solvat

No abstract available

Human HT-29 colon carcinoma cells contain mucarinic M3_3 receptors coupled to phosphoinositide metabolism

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

Syntbesis and Properries of the Selective Antimuscarinic Agent Cyclohexylphenyl(3-piperidinopropyl)silanol

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· lektivität zu einer Standardsubstanz in der experimentellen Pharmakologie bei der Differenzierung von Muskarinrezeptoren geworden.The synthesis of thc selective antimuscarinic agent cyclohexylphenyl(3-piperidinopropyl)silanol (1 b) is described. Starting with (3-chloropropyl)trimethoxysilane, I b was obtained by four reaction steps and isolated as hydrochloride 2b with a total yield of about 45°/o. - Because of its high pharmacological selectivity 1 b has become a reference drug in experimental pharmacology for the differentiation of muscarinic rcceptors

In Vitro Metabolism of Haloperidol and Sila-Haloperidol: New Metabolic Pathways Resulting from Carbon/Silicon Exchange □ S

ABSTRACT: The neurotoxic side effects observed for the neuroleptic agent haloperidol have been associated with its pyridinium metabolite. In a previous study, a silicon analog of haloperidol (sila-haloperidol) was synthesized, which contains a silicon atom instead of the carbon atom in the 4-position of the piperidine ring. In the present study, the phase I metabolism of sila-haloperidol and haloperidol was studied in rat and human liver microsomes. The phase II metabolism was studied in rat, dog, and human hepatocytes and also in liver microsomes supplemented with UDP-glucuronic acid (UDPGA). A major metabolite of haloperidol, the pyridinium metabolite, was not formed in the microsomal incubations with silahaloperidol. For sila-haloperidol, three metabolites originating from opening of the piperidine ring were observed, a mechanism that has not been observed for haloperidol. One of the significant phase II metabolites of haloperidol was the glucuronide of the hydroxy group bound to the piperidine ring. For sila-haloperidol, the analogous metabolite was not observed in the hepatocytes or in the liver microsomal incubations containing UDPGA. If silanol (SiOH) groups are not glucuronidated, introducing silanol groups in drug molecules could provide an opportunity to enhance the hydrophilicity without allowing for direct phase II metabolism. To provide further support for the observed differences in metabolic pathways between haloperidol and sila-haloperidol, the metabolism of another pair of C/Si analogs was studied, namely, trifluperidol and sila-trifluperidol. These studies showed the same differences in metabolic pathways as between sila-haloperidol and haloperidol. Haloperidol was developed in the late 1950s and was found to be a potent neuroleptic agent In the search for analogs of haloperidol, a silicon analog (silahaloperidol) was synthesized, where the quaternary R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom (R 3 SiOH). The synthesis and the physicochemical and pharmacological properties of sila-haloperidol have been reported previously The use of organosilicon chemistry in drug design has been reviewed previousl

Hepatic acute-phase proteins control innate immune responses during infection by promoting myeloid-derived suppressor cell function

Acute-phase proteins (APPs) are an evolutionarily conserved family of proteins produced mainly in the liver in response to infection and inflammation. Despite vast pro- and antiinflammatory properties ascribed to individual APPs, their collective function during infections remains poorly defined. Using a mouse model of polymicrobial sepsis, we show that abrogation of APP production by hepatocyte-specific gp130 deletion, the signaling receptor shared by IL-6 family cytokines, strongly increased mortality despite normal bacterial clearance. Hepatic gp130 signaling through STAT3 was required to control systemic inflammation. Notably, hepatic gp130–STAT3 activation was also essential for mobilization and tissue accumulation of myeloid-derived suppressor cells (MDSCs), a cell population mainly known for antiinflammatory properties in cancer. MDSCs were critical to regulate innate inflammation, and their adoptive transfer efficiently protected gp130-deficient mice from sepsis-associated mortality. The hepatic APPs serum amyloid A and Cxcl1/KC cooperatively promoted MDSC mobilization, accumulation, and survival, and reversed dysregulated inflammation and restored survival of gp130-deficient mice. Thus, gp130-dependent communication between the liver and MDSCs through APPs controls inflammatory responses during infection

Sila-Drugs, 9th Communication [1] Preparation and Properties of Silicon Compounds with Potential Curare-Like Activity, I

Organosilicon compounds 8, 9 and 10 with potential curare-like action and their precursors 0, 6 and 7 were synthesized for the first time. 0-10 were characterized by their physical and chemical properties, and their structures were confirmed by analyses, IH NMR and mass spectroscopy (only for 0-7). The pharmacological and toxicological data of 8, 9 and 10 are reported

Sila-analogues of Meflophenhydramine

Die Sila-Analoga A, 8, C des Antihistaminikums Meflophenhydramin, sowie die Derivate D und E, das Hydrolyseprodukt 8 und die Vorstufen 3-7 wurden dargestellt. Die chemischen und physikalischen Eigenschaften aller Verbindungen und das pharmakologische Verhalten von A-D und 8 wurden untersucht.Sila-analogues A, 8, C of the antihistamine meflophenhydramine as weil as the derivatives D and E, the product of hydrolysis 8 and the precursors 3-7 were synthesized. The chemical and physical properties and the pharmacological behaviour of A-D and 8 are described

Fluorid-induzierte Fragmentierung von Acetyldimethylphenylsilan

Acetyldimethylphenylsilane (2) reacts with TBAF · 3H$_2$O in THF and with KF in DMSO/H$_2$0, respectively, to give [(CH$_3$ )$_2$SiO]$_x$ and 1-Phenylethanol (3) which can be isolated with a nearly quantitative yield. The way 2 reacts with F$^-$ contrasts with that of some aroyl- and heteroaroyltrimethylsilanes, described in the literature. A reaction mechanism is discussed which involves among others a 1 ,2-phenyl shift and a Brook rearrangement.Acetyldimethylphenylsilan (2) reagiert bei Raumtemperatur mit TBAF · 3H$_2$O in THF bzw. mit KF in DMSO/H$_2$O zu [(CH$_3$)$_2$SiO]$_x$ und 1-Phenylethanol (3), welches mit praktisch quantitativer Ausbeute isoliert werden kann. Dieses Reaktionsverhalten von 2 gegenüber F$^-$ weicht drastisch ab von dem in der Literatur beschriebenen Verhalten einiger Aroyl- und Heteroaroyltrimethylsilane. Ein Reaktionsmcchanismus, der u.a. eine 1,2-Phenylverschiebung und eine BrookUmlagerung beinhaltet, wird zur Diskussion gestellt

(Acetoxymethyl)methylphenylgermane: Synthesis, Thermal Behaviour and Olfactoric Properties

No abstract available

Twofold deprotonated citric acid as a bidentate ligand of pentacoordinate silicon: synthesis and structural characterization of the zwitterionic λ5\lambda_5Si-spirosilicate bis[citrato(2-)-O3^3,O4^4][(dimethylammonio)methyl]silicate hydrate

The zwitterionic $\lambda_5$ Si-spirosilicate bis[ citrato(2-)-0$^3$ ,0$^4$ )[ ( dimethylammonio) methyl]silicate (4) was synthesized by reaction of (MeO)$_3$SiCH$_2$NMe$_2$ (3) with citric acid (molar ratio 1 :2) in acetonitrile at room temperature and isolated, after crystallization from water, as the hydrate 4 · H$_2$O (yield 81 %). The crystal structure of 4 · H$_2$O was studied by single-crystal X-ray diffraction. The alcoxide oxygen atoms and central carboxylate oxygen atoms of two citrato(2-) ligands and one carbon atom coordinate to the silicon atom of 4 · H$_2$O. The coordination polyhedron around the pentacoordinate silicon atom (SiO$_4$C framework) can be described as a distorted trigonal bipyramid, the two carboxylate oxygen atoms occupying the axial sites. The $\lambda_5$ Si~silicon(IV) complex 4 also exists in solution (DMSO, H$_2$O)