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Sila-Trifluperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Trifluperidol: Synthesis and Pharmacological Characterization

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posted on 2010-04-12, 00:00 authored by Reinhold Tacke, Binh Nguyen, Christian Burschka, W. Peter Lippert, Alexandra Hamacher, Christian Urban, Matthias U. Kassack
Trifluperidol (2a) is a dopamine (D2) receptor antagonist of the butyrophenone type. Carbon/silicon exchange (sila-substitution) in the 4-position of the piperidine ring of 2a (R3COH → R3SiOH) results in sila-trifluperidol (2b). The silanol 2b was synthesized in a multistep synthesis, starting from triethoxy(vinyl)silane, and was isolated as the hydrochloride 2b·HCl. Compound 2b·HCl was structurally characterized by single-crystal X-ray diffraction and solution NMR spectroscopy, and the stability of the silanol 2b in aqueous solutions at different pH values was studied by ESI-MS experiments. In addition, the pharmacological profiles of the C/Si analogues trifluperidol (2a) and sila-trifluperidol (2b) and of the related compounds haloperidol (1a) and sila-haloperidol (1b) were studied in functional receptor assays at human dopamine D1 and D2 receptors. Sila-substitution of 1a (→ 1b) and 2a (→ 2b) affects the pharmacological properties significantly.