Haloperidol (1 a), a dopamine (D(2)) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1 a (R(3)COH --> R(3)SiOH) leads to sila-haloperidol (1 b). Sila-haloperidol was synthesized in a new multistep synthesis, starting from tetramethoxysilane and taking advantage of the properties of the 2,4,6-trimethoxyphenyl unit as a unique protecting group for silicon. The pharmacological profiles of the C/Si analogues 1 a and 1 b were studied in competitive receptor binding assays at D(1)-D(5), sigma(1), and sigma(2) receptors. Sila-haloperidol (1 b) exhibits significantly different receptor subtype selectivities from haloperidol (1 a) at both receptor families. The C/Si analogues 1 a and 1 b were also studied for 1) their physicochemical properties (log D, pK(a), solubility in HBSS buffer (pH 7.4)), 2) their permeability in a human Caco-2 model, 3) their pharmacokinetic profiles in human and rat liver microsomes, and 4) their inhibition of the five major cytochrome P450 isoforms. In addition, the major in vitro metabolites of sila-haloperidol (1 b) in human liver microsomes were identified using mass-spectrometric techniques. Due to the special chemical properties of silicon, the metabolic fates of the C/Si analogues 1 a and 1 b are totally different.
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 (Janssen et al., 1959). Haloperidol is a dopamine (D 2 ) receptor antagonist and is still used in the treatment of schizophrenia, although it may cause severe extrapyramidal side effects, including parkinsonism and tardive dyskinesia (Levinson, 1991;Casey, 1995). The pyridinium metabolite of haloperidol has been proposed to contribute to these neurotoxic side effects because it structurally resembles 1-methyl-4-phenylpyridinium (commonly referred to as MMP ϩ ), an inducer of Parkinson disease-like symptoms (Subramanyam et al., 1991a;Dauer and Przedborski, 2003).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 (Tacke et al., 2004a(Tacke et al., , 2008. As a minor part of an extensive study of sila-haloperidol, including synthesis and pharmacological properties, three major phase I metabolites in human liver microsomes (HLMs) were tentatively identified. One of these metabolites was proposed to be formed via N-dealkylation and the other two by opening of the piperidine ring (Tacke et al., 2008). Th...
The cover picture shows the structure of the bis[citrato(3Ϫ)]silicate dianion, a hexacoordinate silicon species with two tridentate ligands derived from citric acid. This complex has been synthesized and structurally characterized in context with studies on silica biomineralization. Details are discussed in the Short Communication by R. Tacke et al. on p. 1025 ff.
Octahedral molybdenum chalcogenide clusters are the building blocks of the well-known Chevrel phases. Although the synthesis of molecular Mo 6 S 8 L 6 (L = PEt 3 and pyridine) clusters has been previously reported, a high yield and larger scale synthetic procedure is needed to produce soluble Mo 6 S 8 L 6 (L = Lewis base ligand) clusters, so that they can be used as precursors for the construction of novel network structures. Using the previously developed W 6 S 8 (4tert-butylpyridine) 6 synthesis as a starting point, a facile, high yield (70%) synthesis of Mo 6 S 8 (4-tert-butylpyridine) 6 from (Bu 4 N) 2 Mo 6 Cl 8 Cl 6 was developed. This general sulfidation reaction scheme can be extended to the direct preparation of many M 6 S 8 L 6 (M = W, Mo; L = Lewis base ligand) complexes. Three Mo 6 S 8 L 6 complexes (L = PEt 3 , methylamine, 4,4Ј-bipyridine) were also prepared via ligand exchange reactions with Mo 6 S 8 (4-tert-butylpyridine) 6 . The above Mo 6 S 8 L 6 complexes were characterized and their reactivity was compared with their tungsten counterparts. Crystal structures were found for Mo 6 S 8 (4-tert-butylpyridine) 6 , Mo 6 S 8 (4,4Ј-bipyridine) 6 , and Mo 6 S 8 (methylamine) 6 .
A series of triorganyl(2,4,6-trimethoxyphenyl)silanes containing various combinations of acid-labile protecting groups for silicon, including allyl, 2,6-dimethoxyphenyl, mesityl, 4-methoxyphenyl, 1-naphthyl, and phenyl, were synthesized and characterized. These compounds served as reagents in a series of experiments to determine the selectivity of the cleavage of the 2,4,6-trimethoxyphenyl group in the presence of the aforementioned groups using an ethereal hydrogen chloride solution to obtain synthetically useful chlorosilanes. Additionally, the silylation potential of trimethyl-, methyldiphenyl-, and triethyl(2,4,6-trimethoxyphenyl)silane under mild (0−35 °C), acidic conditions with O-, N-, and S-nucleophiles was examined. These silylation reagents exhibit both chemo- and regioselectivity with respect to the tested nucleophiles, are neither moisture nor air sensitive and thus easy to handle, and produce a relatively inert byproduct, 1,3,5-trimethoxybenzene, which is recyclable.
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