Sila-venlafaxine, a Sila-Analogue of the Serotonin/Noradrenaline Reuptake Inhibitor Venlafaxine:  Synthesis, Crystal Structure Analysis, and Pharmacological Characterization

Abstract

The serotonin/noradrenaline reuptake inhibitor rac-1- [2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]cyclohexan-1-ol (rac-venlafaxine, rac-1a) is in clinical use as an antidepressant. The silicon analogue, rac-1-[2-(dimethylamino)-1-(4-methoxyphenyl)ethyl]-1-silacyclohexan-1-ol (rac-sila-venlafaxine, rac-1b), was synthesized in multistep syntheses, starting from tetrachlorosilane or tetramethoxysilane. The corresponding 1-silacyclopentan-1-ol derivative rac-2 was prepared analogously. The sila-venlafaxine enantiomers (R)-1b and (S)-1b were obtained by resolution of rac-1b, using (+)-or (-)-10camphorsulfonic acid as the resolving agent. Compounds rac-1b, (R)-1b, (S)-1b, rac-1b‚HCl, (R)-1b‚ HCl, (S)-1b‚HCl, (R)-1b‚HBr, rac-2, and rac-2‚HCl were characterized by multinuclear NMR studies and elemental analyses, and rac-1b‚HCl, (R)-1b‚HBr, and rac-2 were additionally characterized by crystal structure analyses. Compounds rac-1a, rac-1b, rac-2, (R)-1a, (S)-1a, (R)-1b, and (S)-1b were tested as their hydrochlorides for their efficacy in serotonin, noradrenaline, and dopamine reuptake inhibition assays. Sila-substitution (C/Si switch) of compounds rac-1a, (R)-1a, and (S)-1a (f rac-1b, (R)-1b, (S)-1b) was found to dramatically influence their pharmacological selectivity profiles with respect to serotonin, noradrenaline, and dopamine reuptake inhibition. (R)-Sila-venlafaxine ((R)-1b) was identified to have a refined selectivity profile consistent with selective noradrenaline reuptake inhibition. Compounds with this profile may provide therapeutic benefit in the treatment of various nervous system disorders.

Sila‐Haloperidol, a Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol: Synthesis, Pharmacological Properties, and Metabolic Fate

“…In addition, crystallographic data (excluding structure factors) for the structures reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication nos. CCDC-661268 (5) and CCDC-661269 (6). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_reques-et.cif.…”

“…[3] With these considerations in mind, we examined the biological effects of sila-substitution (C/Si exchange) [4] of haloperidol (1 a) and thus synthesized its silicon analogue, sila-haloperidol (1 b), [5] whereby the R 3 COH carbon atom in the piperidine ring was replaced by a silicon atom. In context with our systematic research on silicon-based drugs, [6] we carried out a full characterization of 1 b·HCl (solution NMR studies, crystal structure analysis, ESI-MS studies of aqueous solutions) complemented by radioligand binding studies on hD 1 , hD 2 , hD 4 , and hD 5 human dopamine receptors at that time.…”

“…As one of the metabolites of haloperidol (1 a) has been speculated to be responsible for the longterm, irreversible Parkinsonism-like side effects of this drug, [3] we were also interested in the metabolic fate of sila-haloperidol (1 b) and performed comparative in vitro studies of the metabolism of the C/Si analogues 1 a and 1 b using human liver microsomes. This broad spectrum of studies aimed at a representative assessment of the potential of the carbon/silicon switch strategy [4,6] for drug design. In addition to the carbon/silicon switch strategy, it should be mentioned that there are also other ways of applying organosilicon chemistry to drug design.…”

Silicon Analogues of the Nonpeptidic GnRH Antagonist AG‐045572: Syntheses, Crystal Structure Analyses, and Pharmacological Characterization

“…[2,3] It has been shown to act as an allosteric modulator of the GnRH receptor [4] and is highly efficacious in in vivo models of hormone suppression. Replacement of a carbon atom with a silicon atom (sila-substitution) is a novel tool for drug design [5,6] that has already been used in the design of GnRH antagonists. It has been demonstrated that the carefully targeted introduction of silicon into a GnRH antagonist, in this case a peptide, can lead to enhanced bioactivity as a result of improved pharmacokinetics.…”

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

“…Venlafaxine and its silicon analog silavenlafaxine displayed similar physicochemical properties but different pharmacological selectivity profiles (Daiss et al, 2006). Fexofenadine is a histaminic H 1 receptor antagonist used in the treatment of allergies.…”