Quantitative comparison of functional screening by measuring intracellular Ca2+ with radioligand binding at recombinant human dopamine receptors

Kassack, Matthias U.

doi:10.1208/ps040431

Cited by 7 publications

(6 citation statements)

References 42 publications

(31 reference statements)

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“…(b) Cell Culture. Stable cell lines of human embryonic kidney (HEK293) cells (ATCC, Rockville, MD) were generated as previously described. , Briefly, pcDNA3 vectors containing a fragment coding for the entire human hD 1 , hD 2 , and hD 5 dopamine receptors were transfected into HEK293 cells by lipofection with Roti-Fect transfection reagent (Roth, Karlsruhe, Germany). Clonal selection was performed by adding 400 μg/mL G-418 to the culture medium.…”

Section: Methodsmentioning

confidence: 99%

Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol

Tacke¹,

Heinrich²,

Bertermann³

et al. 2004

Organometallics

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Haloperidol (1a), a dopamine (D2) receptor antagonist, is in clinical use as an antipsychotic agent. Carbon/silicon exchange (sila-substitution) at the 4-position of the piperidine ring of 1a (R3 COH → R3 SiOH) leads to sila-haloperidol (1b). Sila-haloperidol was synthesized in a multistep synthesis, starting from tetramethoxysilane, and was isolated as the hydrochloride 1b·HCl. ESI-MS studies of aqueous solutions of the silanol 1b and the corresponding disiloxane 10 at different pH values revealed a remarkable stability of 1b. The C/Si analogues 1a·HCl and 1b·HCl were structurally characterized by single-crystal X-ray diffraction and solution ([D6]DMSO) NMR spectroscopy. Analogous chair conformations of the piperidinium (1a·HCl) and 4-silapiperidinium (1b·HCl) skeleton were observed in the crystal, and two analogous chair conformations of the cations were detected in solution, the molar ratios of these two conformers differing substantially (1a·HCl, 13:1; 1b·HCl, 2:1). In radioligand binding studies, the C/Si analogues 1a and 1b displayed similar potencies at recombinant human dopamine hD1, hD4, and hD5 receptors, whereas the silicon compound 1b was 4.7-fold more potent at hD2 receptors than its carbon analogue 1a; i.e., sila-substitution of haloperidol has changed the receptor selectivity profile.

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Section: Methodsmentioning

confidence: 99%

Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol

Tacke¹,

Heinrich²,

Bertermann³

et al. 2004

Organometallics

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“…b) Cell culture and transfection: HEK293 cells stably expressing hD 1 , hD 2S , or hD 5 dopamine receptors [29,30] were grown in Dulbecco's modified Eagle's Medium Nutrient Mixture F-12 Ham (DMEM/ F-12 1:1 mixture) containing fetal bovine serum (FBS, 10 %), streptomycin (100 mg mL ). Cells were incubated at 37 8C in a humidified atmosphere under 5 % CO 2 .…”

Section: -(4-chlorophenyl)-4-hydroxy-1-[4-oxo-4-(4-fluorophenyl)butymentioning

confidence: 99%

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

et al. 2008

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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.

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“…HEK293 cells stably expressing dopamine hD 1 or hD 2S receptors were established as previously described. , Both cell lines were grown in Dulbecco’s modified Eagle medium (DMEM, GlutaMAX; Invitrogen, Karlsruhe, Germany) containing 100 U/mL penicillin G, 100 μg/mL streptomycin, and 10% fetal bovine serum (FBS). Then 400 μg/mL active G-418 (Calbiochem, San Diego, CA) was added to the medium of the stably transfected cell lines to maintain selection pressure.…”

Section: Methodsmentioning

confidence: 99%

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

et al. 2010

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Trifluperidol (2a) is a dopamine (D 2 ) receptor antagonist of the butyrophenone type. Carbon/ silicon exchange (sila-substitution) in the 4-position of the piperidine ring of 2a (R 3 COH f R 3 SiOH) 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 3 HCl. Compound 2b 3 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 D 1 and D 2 receptors. Sila-substitution of 1a (f 1b) and 2a (f 2b) affects the pharmacological properties significantly.

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Quantitative comparison of functional screening by measuring intracellular Ca2+ with radioligand binding at recombinant human dopamine receptors

Cited by 7 publications

References 42 publications

Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol

Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol

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

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

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Quantitative comparison of functional screening by measuring intracellular Ca2+ with radioligand binding at recombinant human dopamine receptors

Cited by 7 publications

References 42 publications

Sila-haloperidol: A Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol

Sila-haloperidol: A Silicon Analogue of the Dopamine (D2) Receptor Antagonist Haloperidol

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

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

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Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol

Sila-haloperidol: A Silicon Analogue of the Dopamine (D₂) Receptor Antagonist Haloperidol

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

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