title: Sila-haloperidol, a silicon analogue of the dopamine (D2) receptor antagonist haloperidol: synthesis, pharmacological properties, and metabolic fate.
abstract: 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.
authors.affiliation: Universität Würzburg, Institut für Anorganische Chemie, Am Hubland, 97074 Würzburg, Germany. r.tacke@mail.uni-wuerzburg.de
authors.forename: Reinhold
authors.initials: R
authors.lastname: Tacke
authors.forename: Friedrich
authors.initials: F
authors.lastname: Popp
authors.forename: Barbara
authors.initials: B
authors.lastname: Müller
authors.forename: Bastian
authors.initials: B
authors.lastname: Theis
authors.forename: Christian
authors.initials: C
authors.lastname: Burschka
authors.forename: Alexandra
authors.initials: A
authors.lastname: Hamacher
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.forename: Ulrik
authors.initials: U
authors.lastname: Jurva
authors.forename: Eric
authors.initials: E
authors.lastname: Wellner
mesh_terms: D014150:Antipsychotic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D006220:Haloperidol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D017646:Organosilicon Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D017646:Organosilicon Compounds; D003577:Cytochrome P-450 Enzyme System; D006220:Haloperidol