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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 fügher 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.
(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.
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.
Cholinergie agents arepotent modulators of insulin release that aet via musearinie reeeptors. We now investigated the muscarinic receptor subtype present in rat panereatic islets in binding and funetional studies. Binding of 5 nM [ \(^3\)H]N-methylscopolamine ([\(^3\)H]NMS) was half maximal at 30 min. At 60 min, the maximal total bindingwas 1.29% and the non-specifie binding (presence of 100 ,uM atropine) was 0.18% of the total radioaetivity per 10 f.'g islet protein. Unlabelled atropine inhibited [\(^3\)H]NMS binding with an IC50 of ca. 30 nM. The rank order of antagonist high-affinity binding was atropine > sila-hexocyelium methyl sulfate (SiHC; M\(_1\) > M\(_3\) > M\(_2\) ) > pirenzepine (M\(_1\)> M\(_2\) = M\(_3\) ) = methoctramine (M\(_2\) > M\(_1\) > M\(_3\) ). The high-affinity K\(_d\)s were 8.5, 56, 1300 and 1300 nM, respectively. The high affinity Kd of the muscarinie receptor agonist, arecaidine propargyl ester (APE), was 8.1 nM. The EC\(_{50}\) for the biologieal effects of APE on insulin and glucagon secretion was 3.2 and 2.3 nM. The rank order for the high-affinity biological effects of antagonists (inhibition of APE-mediated insulin/ glucagon release) was almost the same as for binding. The data indicate that rat pancreatie islets contain neither an M\(_1\) subtype (high-affinity for pirenzepine) nor an M\(_2\) subtype (high-affinity for methoctramine) receptor. However, the data evidence an M\(_3\) receptor subtype, since SiHC in the absence of the M\(_1\) receptor subtype shows a relatively high affinity to the receptors in rat panereatic islets.
Die Umsetzung von Diphenyl-vinylsilan mit zyklischen sekundären Aminen (z.B. Morpholin) in Gegenwart der entsprechenden Lithium-amide führt zu einer Substitution des an Silicium gebundenen H-Atoms durch eine Aminogruppe und zu einer Addition des Amins an die Vinylgruppe. 2-Thienylphenyl- vinylsilan reagiert jedoch zusätzlich unter Spaltung der Si-e-Bindung und Aminosubstitution der 2-Thienylgruppe.
Sila-Tiemoniumiodid (16b), ein Sila-Analogon des Anticholinergicums Tiemoniumiodid (16a), und das Sila-Analogon 14b der entsprechenden Tiemonium-Base 14a wurden erstmalig synthetisiert.14b und 16b sowie die Vorstufen 10-13 und 15 wurden in ihren physikalischen und chemischen Eigenschaften charakterisiert und in ihrer Struktur durch Elementaranalysen sowie \(^1\)H-NMR- und Massenspektren sichergestellt. Die spasmolytischen Eigenschaften der Paare 14a/14b und 16a/16b wurden am isolierten Meerschweinchendarm vergleichend untersucht.
Twenty silanes of the type R\(^1\)R\(^2\)Si(H)CH\(_2\)OR\(^3\) (A) were syn- and entropy of activation) of these reactions were studied by thesized {R\(^1\), R\(^2\) = Me, Ph, 1-naphthyl, PhCH\(_2\), Me\(_3\)SiCH\(_2\); OR\(^3\) means of düferential scanning calorimetry (DSC). In addition, = OC(O)Me, OC(O)Ph, OC(O)CF\(_3\) , OS(0)\(_2\)CF\(_3\), OP(O)Ph\(_2\), the kinetics of all reactions were investigated by 1H-NMR OC(O)Cl, and studied for their thermal behaviour. The silanes spectroscopy. The transition state of the rearrangement was A undergo a thermally induced rearrangement to give the investigated by an ab initio study based on the model comcorresponding silanes R\(^1\)R\(^2\)Si(OR\(^3\))Me (B). For compounds with pound H\(_3\)SiCH\(_2\)OC(O)H (-> MeH\(_2\)SiOC(O)H]. The theoretical OR3 = OC(O)Cl, an additional decarboxylation takes place to data and the experimentally obtained energetic and kinetic yield the chlorosilanes R1R2Si(Cl)Me. Except for the deriva- data are discussed in terms of mechanistic aspects of the retives with OR\(^3\) = OC(O)Cl, the energetic (reaction enthalpy) arrangement reaction A -> B. and kinetic data (reaction order, frequency factor, enthalpy ...
Sila-Analogues A 2, B 2 and C 2 of the drug mephenhydramine from the class of benzhydryl ethers were synthesized for the first time by the steps shown in scheme 1, and they and their precursors I-V characterized by their physical {table 1) and chemical properties, and their structures confirmed by NMR, n1ass and infrared spectroscopy (tables 3-5). Their physiological effects were investigated a.nd compared -with those of the parent carbon compounds (section 5).
Sila-ana.logues A 2 and B 2 of two drugs from the benzhydryl ether class, chlorphenoxamine and clofenetamine, were synthesized for the first time by the steps shown in scheme 1. They and their precursors I-VI v;rere characterized by their physical (Table 1) and chemical properties and their structures confirmed by n.m.r., mass and infrared spectroscopy (Tab]es 2-5). Their physiological effects were invest.igated and compared with those of the carbon analogues (Chapter 5).