Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D 2 ) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate
2007; Wiley; Volume: 3; Issue: 1 Linguagem: Inglês
10.1002/cmdc.200700205
ISSN1860-7187
AutoresReinhold Tacke, Friedrich Popp, Bárbara Müller, B. Theis, Christian Burschka, Alexandra Hamacher, Matthias U. Kassack, Dirk Schepmann, Bernhard Wünsch, Ulrik Jurva, Eric Wellner,
Tópico(s)Coordination Chemistry and Organometallics
ResumoHaloperidol (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.
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